Piperidine tachykinin receptor antagonists

ABSTRACT

Compounds of formula (I), and salts and prodrugs thereof ##STR1## wherein n is 1, 2 or 3; 
     X represents O or S; 
     Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms optionally substituted by oxo; 
     R 1  is phenyl optionally substituted by 1, 2 or 3 of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, --OR a , SR a , SOR a , SO 2  R a , --NR a  R b , --NR a  COR b , --NR a  CO 2  R b , --CO 2  R a  or --CONR a  R b  ; 
     R 2  is phenyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl, quinolyl, benzhydryl, or benzyl; 
     R 4  and R 5  each independently represent H, halo, C 1-6  alkyl, oxo, CH 2  OR a , CO 2  R a  or CONR a  R b  ; 
     R 8  represents an optionally substituted aromatic heterocycle; and 
     R a  and R b  are H, trifluoromethyl, C 1-6  alkyl or phenyl optionally substituted by C 1-6  alkyl, halo or trifluoromethyl; 
     are tachykinin antagonists useful in medicine.

This invention relates to a class of azacyclic compounds, which areuseful as tachykinin antagonists. More particularly, the compounds ofthe invention comprise an azacyclic ring system substituted by anarylmethyloxy or arylmethylthio moiety.

The tachykinins are a group of naturally-occurring peptides found widelydistributed throughout mammalian tissues, both within the centralnervous system and in the peripheral nervous and circulatory systems.The structures of three known mammalian tachykinins are as follows:

Substance P:

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met- NH₂

Neurokinin A:

His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH₂

Neurokinin B:

Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH₂

For example, substance P is believed inter alia to be involved in theneurotransmission of pain sensations [Otsuka et al, "Role of Substance Pas a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34(published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Actas a Pain Transmitter?" TIPS (Dec. 1987) 8 506-510], specifically in thetransmission of pain in migraine (B. E. B. Sandberg et al, J. Med Chem,(1982) 25 1009; S. L. Shepheard et al., Br. J. Pharmacol. (1993), 108,11-12) and in arthritis [Levine et al in Science (1984) 226 547-549].These peptides have also been implicated in gastrointestinal (GI)disorders and diseases of the GI tract such as tract such asinflammatory bowel disease [Mantyh et al in Neuroscience (1988) 25 (3)817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et alElsevier Scientific Publishers, Amsterdam (1987) page 85)]. It is alsohypothesised that there is a neurogenic mechanism for arthritis in whichsubstance P may play a role [Kidd et al "A Neurogenic Mechanism forSymmetrical Arthritis" in The Lancet, 11 Nov. 1989 and Gronblad et al"Neuropeptides in Synovium of Patients with Rheumatoid Arthritis andOsteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore,substance P is believed to be involved in the inflammatory response indiseases such as rheumatoid arthritis and osteoarthritis [O'Byrne et alin Arthritis and Rheumatism (1990) 33 1023-8]. Other disease areas wheretachykinin antagonists are believed to be useful are allergic conditions[Hamelet et al Can. J. Pharmacol. Physiol. (1988) 66 1361-7],immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball etal, J. Immunol. (1988) 141 (10) 3564-9] vasodilation, bronchospasm,reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 853235-9] and, possibly by arresting or slowing β-amyloid-mediatedneurodegenerative changes [Yankner et al Science, (1990) 250, 279-82] insenile dementia of the Alzheimer type, Alzheimer's disease, and Down'sSyndrome.

Substance P may also play a role in demyelinating diseases such asmultiple sclerosis and amyotrophic lateral. sclerosis [J. Luber-Narodet. al., poster presented at C.I.N.P. XVIIIth Congress, 28th Jun.-2ndJul., 1992], and in disorders of bladder function such as bladderdetrusor hyper-reflexia (Lancet, 16th May, 1992, 1239).

It has furthermore been suggested that tachykinins have utility in thefollowing disorders: depression, dysthymic disorders, chronicobstructive airways disease, hypersensitivity disorders such as poisonivy, vasospastic diseases such as angina and Reynauld's disease,fibrosing and collagen diseases such as scleroderma and eosinophillicfascioliasis, reflex sympathetic dystrophy such as shoulder/handsyndrome, addiction disorders such as alcoholism, stress related somaticdisorders, neuropathy, neuralgia, disorders related to immuneenhancement or suppression such as systemic lupus erythmatosis (Europeanpatent application no. 0 436 334), ophthalmic disease such asconjuctivitis, vernal conjunctivitis, and the like, and cutaneousdiseases such as contact dermatitis, atropic dermatitis, urticaria, andother eczematoid dermatitis (European patent application no. 0 394 989)and emesis (European patent application no. 0 533 280).

In view of their metabolic instability, peptide derivatives are likelyto be of limited utility as therapeutic agents. It is for this reasonthat non-peptide tachykinin antagonists are sought.

European patent application no. 0 436 334 discloses 4- to 7-memberedazacyclic compounds substituted at the 3-position by a substituted aminomoiety. The compounds are said to be tachykinin antagonists.

The present invention provides a compound of formula (I), or a salt orprodrug thereof: ##STR2## wherein n is 1, 2 or 3;

X represents O or S;

Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which mayoptionally be substituted by oxo;

R¹ represents phenyl optionally substituted by 1, 2 or 3 groups selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano, nitro,trifluoromethyl, trimethylsilyl, --OR^(a), SR^(a), SOR^(a), SO₂ R^(a),--NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --CO₂ R^(a) or--CONR^(a) R^(b) ;

R² represents aryl selected from phenyl and naphthyl; heteroarylselected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyland quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroarylmoiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl;

R⁴ and R⁵ may be present on any available carbon atom of the azacyclicring and each independently represent H, halo, C₁₋₆ alkyl, oxo, CH₂OR^(a), CO₂ R^(a) or CONR^(a) R^(b) ;

R⁸ represents an optionally substituted aromatic heterocycle; and

R^(a) and R^(b) each independently represent H, trifluoromethyl, C₁₋₆alkyl or phenyl optionally substituted by C₁₋₆ alkyl, halo ortrifluoromethyl.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups referred to with respect to theabove formula may represent straight, branched or cyclic groups, orcombinations thereof. Thus, for example, suitable alkyl groups includemethyl, ethyl, n- or iso-propyl, n-, sec-, iso- or tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkylgroups such as cyclopropylmethyl; suitable alkenyl groups include vinyland allyl; and suitable alkynyl groups include propargyl.

The term "halo" as used herein includes fluoro, chlorol, bromo and iodo,especially chloro and fluoro.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs",ed. H. Bundgaard, Elsevier, 1985.

The compounds according to the invention may exist both as enantiomersand as diastereomers. In particular, the relative orientation of the 2-and 3-substituents on the azacyclic ring may give rise to cis and transdiastereoisomers, of which the cis stereochemistry is preferred. It isto be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

Preferably n is 2 or 3, more preferably 3.

Preferably X represents O.

Suitably Y represents a hydrocarbon chain of 1 or 2 carbon atomsoptionally substituted by oxo, such as CH₂, C═O, CH(CH₃), CH₂ (C═O) or(C═O)CH₂. Preferably Y represents CH₂, CH(CH₃) or CH₂ (C═O), morepreferably CH₂ or CH(CH₃). A particularly preferred subgroup ofcompounds according to the invention is represented by compounds offormula (I) wherein Y is CH(CH₃).

Preferably R¹ represents substituted phenyl. When R¹ is substitutedphenyl suitable substituents include nitro, trifluoromethyl,trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, C₁₋₆ alkyl such asmethyl, ethyl, i-propyl, i-butyl, t-butyl and cyclopropyl, C₂₋₆ alkenylsuch as vinyl, C₁₋₆ alkoxy such as methoxy, ethoxy and i-propoxy,phenoxy, amino, carboxamido and carbonylmethoxy. Preferably R¹represents phenyl substituted by one or more groups selected from C₁₋₄alkyl, such as methyl and t-butyl, trifluoromethyl and halo such asiodo, bromo chloro and fluoro.

Suitably R¹ represents monosubstituted phenyl, such as 3-substitutedphenyl or, preferably, disubstituted phenyl, such as 3,5-disubstitutedphenyl. Preferably R¹ represents phenyl substituted at the 3-position bytrifluoromethyl or a C₁₋₆ alkyl group such as t-butyl, or3,5-disubstituted phenyl wherein the substituents are independentlyselected from trifluoromethyl, chloro, fluoro, methyl and t-butyl.Preferred values for R¹ include 3,5-bis(trifluoromethyl)phenyl,3,5-dichlorophenyl, 3-t-butyl-5-methylphenyl, 3-chloro-5-methylphenyl,3-t-butyl-5-chlorophenyl, 3-bis(trifluoromethyl)phenyl and3-t-butylphenyl. Particularly preferred is3,5-bis(trifluoromethyl)phenyl.

Suitably R² represents benzhydryl or optionally substituted phenyl, suchas phenyl optionally substituted by halo such as fluoro or chloro,preferably in the 3-position. Preferably R² represents unsubstitutedphenyl or unsubstituted benzhydryl, more preferably unsubstitutedphenyl.

Suitable values for R⁴ and R⁵ include H, C₁₋₆ alkyl, especially methyl,hydroxymethyl and oxo. The substitutents R⁴ and R⁵ may be located on anyavailable carbon atom of the azacyclic ring including, except in thecase where the substituent R⁴ or R⁵ in question represents oxo, C-2 andC-3. Preferably at least one of R⁴ and R⁵ represents H. In one preferredgroup of compounds R⁴ and R⁵ both represent H. In a further preferredgroup of compounds one of R⁴ and R⁵ is H and the other of R⁴ and R⁵ ismethyl, preferably 2-methyl.

When R⁸ represents a substituted aromatic heterocycle, suitablesubstituents in the heterocyclic ring include one or more of C₁₋₆ alkyl,C₁₋₆ alkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NR^(a) R^(b),NR^(a) COR^(b), CONR^(a) R^(b), CO₂ R^(a), SR^(a), SO₂ R^(a) and CH₂OR^(a), where R^(a) and R^(b) are as previously defined. Particularexamples of suitable substituents include methyl, methoxy, phenyl, oxo,thioxo, bromo, iodo, NH₂, SCH₃, CONH₂ and cyano. Particularly preferredsubstituents include oxo and NH₂.

Suitable values for R⁸ include thienyl, furyl, pyrrolyl, pyridyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl,benzothiophenyl, benzofuranyl and indolyl, any of which may besubstituted.

In particular, R⁸ may represent optionally substituted thienyl, furyl,pyridyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl,benzimidazolyl or benzoxazolyl.

In one group of compounds according to the invention R⁸ representsoptionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl,pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, imidazolyl,benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl or indolyl.

Preferably R⁸ represents a substituted or unsubstituted 5- or 6-memberednitrogen containing aromatic heterocycle such as for example oxazolyl,oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazolyl, pyrazinyl,pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl. Morepreferably R⁸ represents optionally substituted oxazolyl, oxadiazolyl,imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinylor triazinyl, or tetrazolyl substituted by C₁₋₆ alkyl, preferablymethyl.

In one preferred group of compounds according to the invention, R⁸represents substituted or unsubstituted oxadiazolyl, for example,oxadiazolyl substituted by halo, amino, dialkylamino or methyl. Morepreferably R⁸ represents 5-(3-aminooxadiazolyl).

In a further preferred group of compounds according to the invention, R⁸represents substituted or unsubstituted triazolyl, for example,unsubstituted triazolyl or triazolyl subtituted by oxo or thioxo, morepreferably, triazolyl substituted by oxo.

It will be appreciated that, when the heterocyclic moiety R⁸ issubstituted by an oxo or thioxo substituent, different tautomeric formsare possible so that the substituent may be represented as ═O or --OH,or ═S or --SH, respectively. For the avoidance of doubt, all suchtautomeric forms are embraced by the present invention.

One subgroup of compounds according to the invention is represented bycompounds of formula (IA), and salts and prodrugs thereof: ##STR3##wherein n is 1, 2 or 3 and where any carbon atom of (CH₂)_(n) may besubstituted by R¹² and/or R¹³ ;

X represents O or S;

R¹⁰ represents phenyl optionally substituted by 1, 2 or 3 groupsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(c), SR^(c), SOR^(c), SO₂R^(c), --NR^(c) R^(d), --NR^(c) COR^(d), --NR^(c) CO₂ R^(d), --CO₂ R^(c)or --CONR^(c) R^(d) ;

R¹¹ represents aryl selected from phenyl and naphthyl; heteroarylselected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyland quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroarylmoiety may be substituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo ortrifluoromethyl;

R¹² and R¹³ each independently represent H, halo, C₁₋₆ alkyl, oxo, CO₂R^(c) or CONR^(c) R^(d) ;

R¹⁴ represents C₁₋₄ alkyl, optionally substituted by oxo, substituted byan optionally substituted aromatic heterocycle; and

R^(c) and R^(d) each independently represent H, C₁₋₆ alkyl, phenyloptionally substituted by C₁₋₆ alkyl or halo or trifluoromethyl.

Suitable values for the heterocyclic moiety of R¹⁴ include thienyl,furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl,quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl,benzothiophenyl, benzofuranyl and indolyl.

In one sub-class of compounds of formula (IA), R^(c) and R^(d) eachindependently represent H, C₁₋₆ alkyl, phenyl or trifluoromethyl.

A further subclass of compounds of formula (IA) is represented bycompounds wherein n is 2 or 3; R¹² and R¹³ each independently representH, halo, C₁₋₆ alkyl, CO₂ R^(c) or CONR^(c) R^(d) ; R¹⁴ represents C₁₋₄alkyl substituted by an optionally substituted 5- or 6-membered aromaticheterocycle; and R^(c) and R^(d) each independently represent H, C₁₋₆alkyl, phenyl or trifluoromethyl. For the compounds of this subclass,suitable values for the heterocyclic moiety of R¹⁴ include thienyl,furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl andimidazolyl.

A preferred sub-class of compounds according to the invention isrepresented by compounds of formula (IB), and salts and prodrugsthereof: ##STR4## wherein X represents O or S, preferably O;

Y is as defined for formula (I), preferably C₁₋₂ alkyl optionallysubstituted by oxo, more preferably CH₂ or CH(CH₃);

R² represents phenyl or benzhydryl wherein any of the phenyl rings ofthe phenyl or benzhydryl moieties may optionally be substituted by haloor trifluoromethyl, preferably unsubstituted phenyl;

R⁸ is as defined for formula (I); and

R²⁰ and R²¹ independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, bromo, chloro, fluoro, iodo, cyano, nitro, trifluoromethyl,trimethylsilyl, OR^(a), SR^(a) SOR^(a), SO₂ R^(a), NR^(a) R^(b), NR^(a)COR^(b), NR^(a) CO₂ R^(b), COR^(a), CO₂ R^(a) or CONR^(a) R^(b), whereR^(a) and R^(b) are as previously defined; and

z is 1 or 2.

Particular values of R²⁰ and R²¹ include H, methyl, t-butyl, methoxy,i-propoxy, chloro, fluoro, nitro, amino, carbonylmethoxy, carboxamidoand trifluoromethyl. Preferably R²⁰ and R²¹ are both other than H, morepreferably C₁₋₆ alkyl, halo or trifluoromethyl, and are located at the3- and 5-positions of the phenyl ring.

One sub-class of compounds according to the invention are compounds offormula (IB) wherein R⁸ is optionally substituted pyrrolyl, pyrazolyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl,benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, indolyl,thiadiazolyl or oxadiazolyl, more preferably oxadiazolyl.

A further sub-class of compounds according to the invention arecompounds of formula (IB) wherein R⁸ is optionally substitutedoxadiazolyl, pyridinyl, benzimidazolyl, tetrazolyl, thiazolyl, furyl,thienyl, triazolyl, thiadiazolyl, benzoxazolyl, oxazolyl, pyrazinyl,pyridazinyl, triazinyl, pyrimidinyl or imidazolyl.

A particularly preferred group of compounds according to the inventionare compounds of formula (Ia) wherein R⁸ is optionally substitutedtriazolyl, especially triazole substituted by oxo.

For use in medicine, the salts of the compounds of formula (I) will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds according to the invention (such asthe dibenzoyltartrate salts) or of their pharmaceutically acceptablesalts. Suitable pharmaceutically acceptable salts of the compounds ofthis invention include acid addition salts which may, for example, beformed by mixing a solution of the compound according to the inventionwith a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulphuric acid, oxalic acid, fumaric acid, maleicacid, succinic acid, acetic acid, citric acid, tartaric acid, carbonicacid, phosphoric acid or p-toluenesulphonic acid. Salts of amine groupsmay also comprise quaternary ammonium salts in which the amino nitrogenatom carries a suitable organic group such as an alkyl, alkenyl, alkynylor aralkyl moiety. Furthermore, where the compounds of the inventioncarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof may include metal salts such as alkali metal salts, e.g. sodiumor potassium salts; and alkaline earth metal salts, e.g. calcium ormagnesium salts.

Preferred salts of the compounds according to the invention include thehydrochloride and p-toluenesulphonic acid salts.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, solutions or suspensions, or suppositories, for oral,parenteral or rectal administration, or administration by inhalation orinsufflation.

The invention further provides a process for the preparation of apharmaceutical composition comprising a compound of formula (I), or asalt or prodrug thereof, and a pharmaceutically acceptable carrier,which process comprises bringing a compound of formula (I), or a salt orprodrug thereof into association with a pharmaceutically acceptablecarrier.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 500 mg of the active ingredient of thepresent invention. The tablets or pills of the novel composition can becoated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinylpyrrolidone or gelatin.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as set outabove. Preferably the Compositions are adminsitered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably sterile pharmaceutically acceptable solvents may be nebulisedby use of inert gases. Nebulised solutions may be breathed directly fromthe nebulising device or the nebulising device may be attached to a facemask, tent or intermittent positive pressure breathing machine.Solution, suspension or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The compounds of formula (I) are of value in the treatment of a widevariety of clinical conditions which are characterised by the presenceof an excess of tachykinin, in particular substance P, activity. Thesemay include disorders of the central nervous system such as anxiety,depression, psychosis and schizophrenia; neurodegenerative disorderssuch as dementia, including senile dementia of the Alzheimer type,Alzheimer's disease and Down's syndrome; demyelinating diseases such asmultiple sclerosis (MS) and amyotropic lateral sclerosis (ALS; LouGehrig's disease) and other neuropathological disorders such asperipheral neuropathy, for example, diabetic or chemotherapy-inducedneuropathy, and postherpetic and other neuralgias; respiratory diseasessuch as chronic obstructive airways disease, bronchopneumonia,bronchospasm and asthma; inflammatory diseases such as inflammatorybowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoidarthritis; allergies such as eczema and rhinitis; hypersensitivitydisorders such as poison ivy; ophthalmic diseases such asconjunctivitis, vernal conjunctivitis, and the like; cutaneous diseasessuch as contact dermatitis, atropic dermatitis, urticaria, and othereczematoid dermatitis; addiction disorders such as alcoholism; stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; dysthymic disorders; adverse immunologicalreactions such as rejection of transplanted tissues and disordersrelated to immune enhancement or suppression such as systemic lupuserythematosis; gastrointestinal (GI) disorders and diseases of the GItract such as disorders associated with the neuronal control of viscerasuch as ulcerative colitis, Crohn's disease and incontinence; emesis,including acute, delayed and anticipatory emesis, for example, inducedby chemotherapy, radiation, toxins, pregnancy, vestibular disorders,surgery, migraine and variations in intercranial pressure; disorders ofbladder function such as bladder detrusor hyper-reflexia; fibrosing andcollagen diseases such as scleroderma and eosinophilic fascioliasis;disorders of blood flow caused by vasodilation and vasospastic diseasessuch as angina, migraine and Reynaud's disease; and pain or nociception,for example, that attributable to or associated with any of theforegoing conditions, especially the transmission of pain in migraine.For example, the compounds of formula (I) may suitably be used in thetreatment of disorders of the central nervous system such as anxiety,psychosis and schizophrenia; neurodegenerative disorders such as seniledementia of the Alzheimer type, Alzheimer's disease and Down's syndrome;respiratory diseases, particularly those associated with excess mucussecretion, such as chronic obstructive airways disease,bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, andbronchospasm; inflammatory diseases such as inflammatory bowel disease,osteoarthritis and rheumatoid arthritis; adverse immunological reactionssuch as rejection of transplanted tissues; gastrointestinal (GI)disorders and diseases of the GI tract such as disorders associated withthe neuronal control of viscera such as ulcerative colitis, Crohn'sdisease and incontinence; disorders of blood flow caused byvasodilation; and pain or nociception, for example, that attributable toor associated with any of the foregoing conditions or the transmissionof pain in migraine.

The compounds of formula (I) are particularly useful in the treatment ofpain or nociception and/or inflammation and disorders associatedtherewith such as, for example, neuropathy, such as diabetic andchemotherapy-induced neuropathy, postherpetic and other neuralgias,asthma, osteroarthritis, rheumatoid arthritis and especially migraine.

The present invention further provides a compound of formula (I) for usein therapy.

According to a further or alternative aspect, the present inventionprovides a compound of formula (I) for use in the manufacture of amedicament for the treatment of physiological disorders associated withan excess of tachykinins, especially substance P.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of formula (I) or a composition comprising acompound of formula (I).

For the treatment of certain conditions it may be desirable to employ acompound according to the present invention in conjunction with anotherpharmacologically active agent. For example, for the treatment ofrespiratory diseases such as asthma, a compound of formula (I) may beused in conjunction with a bronchodilator, such as a β₂ -adrenergicreceptor antagonist or tachykinin antagonist which acts at NK-2receptors. The compound of formula (I) and the bronchodilator may beadministered to a patient simultaneously, sequentially or incombination.

The present invention accordingly provides a method for the treatment ofa respiratory disease, such as asthma, which method comprisesadministration to a patient in need thereof of an effective amount of acompound of formula (I) and an effective amount of a bronchodilator.

The present invention also provides a composition comprising a compoundof formula (I), a bronchodilator, and a pharmaceutically acceptablecarrier.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day,in particular about 0.01 to about 25 mg/kg, such as from about 0.05 toabout 10 mg/kg of a compound of formula (I) per day. For example, in thetreatment of conditions involving the neurotransmission of painsensations, a suitable dosage level is about 0.001 to 25 mg/kg per day,preferably about 0.005 to 10 mg/kg per day, and especially about 0.005to 5 mg/kg per day. The compounds may be administered on a regimen of 1to 4 times per day, preferably once or twice per day.

According to one general process (A), the compounds according to theinvention may be prepared by a process which comprises reacting acompound of formula (II): ##STR5## wherein R¹, R², R⁴, R⁵, X and n areas defined for formula (I) above, with a reagent suitable to introducethe group Y--R⁸, for example, a halide or acyl halide, or correspondingmesylate or tosylate, of formula R⁸ --Y--L, where L represents halo,such as chloro, bromo or iodo, methylsulphonate orp-toluenesulphonate,or any other suitable leaving group, in the presenceof a base.

Suitable bases of use in the reaction include inorganic bases such asalkali metal carbonates, for example, potassium carbonate.

Conveniently the reaction is effected in a suitable organic solvent, forexample, dimethylformamide.

According to a second process (B), compounds of formula (I) wherein R⁸represents 5-oxadiazolyl may be prepared by reaction of a compound offormula (III) with a compound of formula (IV): ##STR6## wherein R¹, R²,R⁴, R⁵, X, Y and n are as defined for formula (I), R³⁰ represents analkyl group and R³¹ represents H or a suitable substituent such as C₁₋₆alkyl, C₁₋₆ alkoxy, halo, NR^(a) R^(b) or NR^(a) COR^(b), where R^(a)and R^(b) are as previously defined, in the presence of a base.

Suitable bases of use in the reaction include alkali metals, such as,for example, sodium, and alkali metal hydrides, such as, for example,sodium hydride.

The reaction is conveniently effected in a suitable organic solvent.Which solvents will be appropriate will depend on the nature of the baseused. For example, where the base used is an alkali metal, suitablesolvents will include alcohols, for example, ethanol, whereas where thebase used is an alkali hydride, suitable solvents will include ethers,for example, tetrahydrofuran.

Preferably the reaction is conducted at elevated temperature, such asthe reflux temperature of the chosen solvent.

According to a further process, (C), compounds of formula (I) wherein R⁸represents tetrazolyl may be prepared from intermediates of formula (V):##STR7## wherein R¹, R², R⁴, R⁵, X, Y and n are as defined for formula(I) by treatment with an alkali metal azide, such as sodium azide.

The reaction is conveniently effected in a high boiling organic solvent,such as, for example, N-methylpyrrolidinone,

According to a further process, (D), compounds of formula (I) wherein R⁸represents thiazolyl may be prepared from intermediates of formula (VI):##STR8## wherein R¹, R², R⁴, R⁵, X, Y and n are as defined for formula(I), by reaction with a compound of formula Hal--CH₂ C(O)--R⁶⁰, whereHal represents halo, such as bromo, chloro or iodo, and R⁶⁰ represents Hor a suitable substituent such as C₁₋₆ alkyl.

The reaction is conveniently effected in a suitable organic solvent,such as a ketone, for example, acetone, or an alcohol, for example,methanol, or a mixture of solvents, preferably at elevated temperature,such as the reflux temperature of the chosen solvent.

According to a further process, (E), compounds of formula (I) wherein R⁸represents thioxotriazolyl may be prepared from intermediates of formula(VII) ##STR9## wherein R¹, R², R⁴, R⁵, X, Y and n are as defined forformula (I), by reaction with a compound of formula R⁶¹ NCS, wherein R⁶¹represents H or a suitable substituent such as C₁₋₆ alkyl, in thepresence of a base.

Suitable bases of use in the reaction include organic bases such as, forexample, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction isconveniently effected in a suitable orgainc solvent, such as alcohol,e.g. butanol.

According to a further process, (F), compounds of formula (I) wherein R⁸represents unsubstituted or substituted triazolyl may be prepared byreaction of intermediates of formula (II) with a compound of formula(VIII): ##STR10## wherein Y and Hal are as previously defined and R¹⁸ isH or a group suitable as a substituent of the triazole ring, orconvertible to such a group under the reaction conditions, in thepresence of a base.

Suitable bases of use in the reaction include alkali metal carbonates,such as, for example, potassium carbonate.

Suitably R¹⁸ represents H, OCH₃ (which is converted to an oxosubstituent under the reaction conditions) or CONH₂.

The reaction is conveniently effected in an anhydrous organic solvent,such as, for example, anhydrous dimethylformamide, preferably atelevated temperature, such as about 140° C.

According to a further process, (G), compounds of formula (I) wherein R⁸represents substituted or unsubstituted 1,3,5-triazine may be preparedby reaction of intermediates of formula (IX): ##STR11## wherein R¹, R²,R⁴, R⁵, X, Y and n are as defined for formula (I), with substituted orunsubstituted 1,3,5-triazine.

The reaction is conveniently effected in a suitable organic solvent,such as acetronitrile, at elevated temperature, such as 80°-90° C.,preferably about 82° C.

According to a further process, (H), compounds of formula (I) wherein R⁸represents substituted or unsubstituted 1,2,5-triazine may be preparedby reaction of an intermediate of formula (X) with a dicarbonyl compoundof formula (XI): ##STR12## wherein R¹, R², R⁴, R⁵, X, Y and n are asdefined for formula (I) and R³⁵ and R³⁶ each independently represnt H ora suitable substituent such as C₁₋₆ alkyl, e.g. methyl.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, e.g. tetrahydrofuran, conveniently at ambienttemperature.

Further details of suitable procedures will be found in the accompanyingExamples.

Compounds of formula (VIII) may be prepared as described in J. Med.Chem, 27, (1984), 849.

Compounds of formula (I) may also be prepared from other compounds offormula (I) using suitable interconversion procedures. For example,compounds of formula (I) wherein Y represents C₁₋₄ alkyl substituted byan aromatic heterocycle may be prepared from compounds of formula (I)wherein Y represents C₁₋₄ alkyl substituted by oxo by reduction, forexample, using borane. Suitable interconversion procedures are describedin the accompanying Examples, or will be readily apparent to thoseskilled in the art.

Intermediates of formula (III) may be prepared from intermediates offormula (II) by reaction with a compound of formula Hal--Y--CO₂ R³⁰,where Hal represents halo such as chloro, bromo or iodo and R³⁰ and Yare as above defined, in the presence of a base. Suitable bases includetertiary amines, for example, triethylamine. Conveniently the reactionis effected in a suitable organic solvent, such as an ether, forexample, tetrahydrofuran, at elevated temperature, such as the refluxtemperature of the solvent.

Intermediates of formula (IV) are commercially available or may beprepared from commercially available materials by conventionalprocedures well-known to those skilled in the art.

Intermediates of formula (II) may be prepared as described in publishedEuropean patent application no. 0 528 495.

Intermediates of formula (V) may be prepared from intermediates offormula (II) by reaction with a compound of formula Hal--Y--CN, whereinHal is halo such as bromo, chloro or iodo and Y is as previouslydefined.

Intermediates of formula (VI) may be prepared from intermediates offormula (V) by treatment with an alkylthioamide, such as, for example,thioacetamide.

Intermediates of formula (VII) may be prepared from intermediates offormula (III) by treatment with hydrazine. The reaction is convenientlyeffected in a suitable organic solvent, such as an alcohol, for example,ethanol, at elevated temperature.

Intermediates of formula (IX) may be prepared from intermediates offormula (II) by reaction with a compound of formula Hal--Y--C(NH)NH₂,where Hal and Y are as previously defined.

Intermediates of formula (X) may be prepared from intermediates offormula (II) by reaction with a compound of formulaHal--Y--C(NH)NHNH--Boc, wherein Hal and Y are as previously defined andBoc stands for t-butoxycarbonyl, followed by deprotection under acidicconditions.

Compounds of formula (XI) are commercially available or may be preparedfrom commercially available compounds by known methods.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. For example, any suitable intermediates may be resolved intotheir component enantiomers by standard techniques, such as theformation of diastereomeric esters or amides, followed bychromatographic separation or separation by fractional crystallizationand removal of the chiral auxiliary. The diastereomeric intermediatescan then be used to prepare optically pure compounds of formula (I).

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds accordingto the invention.

The substance P antagonising activity of the compounds described hereinwas evaluated using the human NK1R assay described in published Europeanpatent application no. 0 528 495. The method essentially involvesdetermining the concentration of the test compound required to reduce by50% the amount of radiolabelled substance P binding to human NK1R,thereby affording an IC₅₀ value for the test compound. The compounds ofExamples 1-10, for example, were found to have IC₅₀ values less than 500nM.

DESCRIPTION 1:cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinehydrochloride salt

a) A solution of methyl 4-nitrobutyrate (23 g) and benzaldehyde (16 ml)in acetic add (39 ml) containing ammonium acetate (12.12 g) was heatedat reflux under nitrogen for 2 h. The reaction mixture was cooled to 5°C., whereby a pale-yellow solid crystallised. This was isolated byfiltration, then dissolved in dichloromethane, washed cautiously withsaturated aqueous sodium bicarbonate solution (2×), then dried (MgSO₄)and concentrated to leave a yellow solid. Recrystallisation from ethylacetate provided 5-nitro-2-oxo-6-phenylpiperidine (12.5 g) as acrystalline, white solid. ¹ H NMR (CDCl₃) d 7.46-7.26 (m), 6.0 (br s),5.24 (dd, J=1.4, 7.0 Hz), 4.70 (m), 2.70-2.50 (m), 2.38-2.24 (m).

b) Potassium t-butoxide (1.68 g) was added to a solution of5-nitro-2-oxo-6-phenylpiperidine (3 g) in a mixture of dichloromethane(50 ml) and methanol (50 ml) and the mixture was cooled to -78° C. undernitrogen. Ozone was bubbled through the solution for 3 h. A yellow-greensolution resulted, and TLC indicated no starting material remained. Thereaction mixture was purged with oxygen for 5 min to remove excessozone, then dimethylsulfide (7 ml) was added and the reaction mixturewas allowed to warm to 23° C. The solvent was removed in vacuo, and theresidue was partitioned between dichloromethane and water. The layerswere separated, and the aqueous phase was extracted twice withdichloromethane. The combined organic extracts were washed with brine,then dried (K₂ CO₃) and concentrated to leave a yellow solid.

This crude material was slurried in dry tetrahydrofuran and added tolithium aluminium hydride (1M in THF, 50 ml) then heated at reflux for12 h. After cooling to 23° C., the reaction mixture was quenched by thecautious addition of water (dropwise) under nitrogen, then 2M sodiumhydroxide. The mixture was filtered through a pad of Hyflo, the filtratewas washed with brine, then dried (K₂ CO₃) and concentrated to leave ayellow solid. Purification by silica-gel chromatography (CH₂ Cl_(2/)MeOH/NH₃ 97:3:1 then CH₂ Cl_(2/) MeOH 95:5) provided3-hydroxy-2-phenylpiperidine as a ca 4:1 mixture of cis- andtrans-isomers respectively. ¹ H NMR (CDCl₃) 7.44-7.20 (m), 3.84 (2),3.76 (s), 3.54 (m), 3.4 (s), 3.3 (d, J=8 Hz), 3.26 (m), 3.04 (m) 2.78(ddd, J=2.9, 11.9, 11.9 Hz), 2.70 (ddd, J=2.9, 11.9, 11.9 Hz), 2.18-1.78(m), 1.48 (m). MS (EI) m/z 177 (M⁺).

c) Di-t-butyldicarbonate (1.36 g) was added to a solution of3-hydroxy-2-phenylpiperidine (1 g) in dichloromethane (8 ml) undernitrogen and the mixture stirred at 23° C. for 3 h. The solvent wasremoved in vacuo, and the residue purified by silica-gel chromatography(CH₂ Cl₂ /MeOH/NH₃ 97:3:0.5) to provide cis- andtrans-1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (1.4 g) as aclear, viscous oil. ¹ H NMR (CDCl₃) d 7.50-7.42 (m), 7.40-7.14 (m), 5.36(d, J=5.6 Hz), 4.50 (m), 4.44 (m), 4.12-3.92 (m), 3.02 (ddd, J=3.0,12.5, 12.5 Hz), 2.87 (ddd, J=3.0, 12.5, 12.5 Hz), 1.88-1.66 (m), 1.46(s), 1.36 (s).

d) To a cooled (0° C.) solution of1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (1.4 g) in drydimethylformamide (5 ml) was added sodium hydride (80% dispersion inmineral oil; 182 mg). The cooling bath was removed and the reactionmixture stirred at 23° C. for 30 min. A solution of3,5-bis(trifluoromethyl)benzyl bromide (1.87 g) in dry dimethylformamide(1 ml) was added and stirring was continued for 2 h at room temperature.The mixture was diluted with water (100 ml) and extracted with ethylacetate (3×40 ml). The combined organic extracts were washed with brine(1×30 ml), dried (MgSO₄) and evaporated to yield a pale yellow oil.Purification by chromatography on silica using gradient elution ofhexane in ethyl acetate (9:1-4:1) afforded the productcis-1-t-butyloxycarbonyl-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine(350 mg) as an oil. ¹ H NMR (250 MHz, CDCl₃) d 7.77 (1H, s, ArH), 7.71(2H, s, ArH), 7.53-7.57 (2H, m, ArH), 7.2-7.4 (3H, m, ArH), 5.70 (1H, brd, app. J=7.0 Hz, NCHPh), 4.73 (2H, brs, OCH₂), 3.84-3.98 (2H, m,NCHCHO+NCHH), 2.77 (1H, ddd, J=13.0, 13.0, 3.0 Hz), NCHH), 2.00 (2H, mc,CH₂), 1.6-1.8 (2H, m, CH₂), 1.40 (9H, s, C(CH₃)₃).

e) Trifluoroacetic acid (3 ml) was added to the product of (d) above(800 mg) under nitrogen and the resulting solution was stirred for 1 h.Excess trifluoroacetic acid was removed in vacuo and the residue waspartitioned between 2M sodium hydroxide and dichloromethane. The organicphase was washed with brine, dried (MgSO₄) and evaporated to afford acolourless oil. Purification on silica (dichloromethane in methanol,98:2-95:5) afforded the productcis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidine (360mg) as a colourless oil. ¹ H NMR (360 MHz, CDCl₃) d 7.78 (1H, s, ArH),7.44 (2H, s, ArH), 7.18-7.38 (5H, s, ArH), 4.52 (1H, d, J=12.5 Hz,OCHH), 4.13 (1H, d, J=12.5 Hz, OCHH), 3.84 (1H, d, J=1.0 Hz, NCHPh),3.68 (1H, d, J=1.5 Hz), 3.28 (1H, m, NCHCHO), 2.84 (1H, ddd, J=3.0,12.5, 12.5 Hz, NCHH), 2.20 (1H, m, NCHH), 1.8-1.98 (2H, m, CH₂),1.64-1.78 (1H, m, CHH), 1.50-1.58 (1H, m, CHH); MS m/z 404 ((M+1)⁺,90%).

The oil was dissolved in ether to which was added excess etherealhydrogen chloride. Upon standing a white solid crystallised. This wasfiltered and recrystallised from ethyl acetate-methanol to afford thetitle compound as white crystals: mp 200°-203° C. ¹ H NMR (360 MHz,DMSO) d 7.95 (1H, s, ArH), 7.81 (2H, s, ArH), 7.37-7.47 (5H, m, ArH),4.78 (1H, d, J=13.0 Hz, OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J=13.0Hz, OCHH), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J=13.0 Hz, NCHH), 2.23(1H, d, J=13.0 Hz, NCHH), 1.64-2.00 (4H, m, CH₂ ×2); MS (CI⁺) m/z 404((M+1)⁺, 90%); Found: C, 54.08; H, 4.47; ⁻ N, 3.13. Calcd. for C₂₀ H₂₀F₆ NOCl.0.25H₂ O: C, 54.06; H, 4.65; N, 3.15%.

DESCRIPTION 2:(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(carbomethoxy)methyl-2-phenylpiperidine

cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinehydrochloride (Description 1,1 g) was liberated from the hydrochloridesalt by partitioning between ethyl acetate and 2M sodium hydroxide. Theorganic phase was washed successively with water, saturated brine, dried(MgSO₄) and evaporated in vacuo. To a solution of the residual oil intetrahydrofuran (20 ml) was added triethylamine (0.4 ml) and methylbromoacetate (400 mg) and the solution was heated at reflux under anatmosphere of nitrogen for 16 h. To the cooled solution was added ethylacetate and water and the organic phase washed further with water anddried (MgSO₄). After the solvent had been removed in vacuo the residuewas chromatographed on silica gel eluting with ethyl acetate/petroleumether (3:10). The product was recrystallised from diethylether/petroleum ether to give the title compound: mp 81°-83° C. Found:C, 57.35; H, 4.98; N, 2.84; C₂₃ H₂₃ F₆ NO₃.0.1(H₂ O) requires C, 57.71;H, 4.86; N, 2.93%. MS (CI.sup. +) m/z 476 (M+H)⁺.

DESCRIPTION 3:(+)-(2S,3S)-cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidinehydrochloride salt

a) The mixture of cis- and trans-isomers of 3-hydroxy-2-phenylpiperidine(Description 1, (2b)) and 4-toluenesulfonic acid monohydrate wascrystallized from methanol/ethyl acetate to givecis-3-hydroxy-2-phenylpiperidinium tosylate: mp 266°-267° C.

b) The tosylate salt (Description 3(a) above) was dissolved in a mixtureof ethyl acetate and 10% aqueous Na₂ CO₃ with warming. The organic phasewas washed with saturated brine, dried (K₂ CO₃) and evaporated to givecrystalline cis-3-hydroxy-2-phenylpiperidine, mp 110°-110.5° C.

c) cis-3-Hydroxy-2-phenylpiperidine (Description 3b) and(-)dibenzoyltartrate were dissolved in methanol and crystallized byaddition of ethyl acetate. The solid was recrystallised from hotmethanol to give the hemi dibenzovltartrate salt: mp 223°-224° C. Thiswas liberated from the salt as described above to give the singleenantiomer (+)-cis-3-hydroxy-2-phenylpiperidine, mp 93°-95° C. [a]²³_(D) =+98.5° (c=1, MeOH). The mother liquors were converted to the freebase as described in Description 3b and crystallization using(+)dibenzoyltartrate in an analogous manner to that described above gave(-)-3-hydroxy-2-phenylpiperidine, mp 93°-95° C. [a]²³ _(D) =-97.2° (c=1,MeOH).

d) (+)-cis-3-Hydroxy-2-phenylpiperidine was reacted according to theprocedure detailed in Description 1c-e to give(+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidinehydrochloride as a crystalline solid: mp 215°-216° C. [a]_(D) =+87.3°(c=1, MeOH). ¹ H NMR (360 MHz, DMSO-d₆) d 7.95 (1H, s, ArH), 7.81 (1H,s, ArH), 7.47 (2H, m, ArH), 7.37 (3H, m, ArH), 4.78 (1H, d, J=13.0 Hz,OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J=13.0 Hz, OCHH), 3.96 (1H, s,NCHCHO), 3.10 (1H, t, J=13.0 Hz, NCHH), 2.23 (1H, d, J=13.0 Hz, NCHH),2.00-1.64 (4H, m, CH₂ ×2); MS (CI⁺) m/z 404 (M+1⁺ 90%); Found: C, 54.52;H, 4.60; N, 3.11. Calcd. for C₂₀ H₁₉ F₆ NO.HCl: C, 54.62; H, 4.58; N,3.18%.

DESCRIPTION 4:(+)-(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(carbomethoxy)methyl-2-phenylpiperidine

The title compound was prepared from(+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine(Description 3) using the procedure detailed in Description 2: mp60°-70° C. [a]_(D) =+132.3° (c=1, MeOH). ¹ H NMR (360 MHz, CDCl₃) d1.57-1.63 (3H, m, CH₂ +CHH), 2.04-2.17 (2H, m, CHH, CHHN), 3.07-3.10(1H, m, NCHCHO), 3.20 (1H, d, J=17.0 Hz, NCHHCO₂ CH₃), 3.31 (1H, d,J=17.0 Hz, NCHH CO₂ CH₃), 3.58 (3H, s, CH₃), 3.93 (1H, s, NCHPh), 4.07(1H, d, J=12.0 Hz, OCHH), 4.49 (1H, d, J=12.0 Hz, OCHH), 7.28-7.34 (3H,m, ArH), 7.43-7.45 (2H, m, ArH), 7.54 (2H, s, ArH), 7.71 (1H, s, ArH).MS (CI⁺) m/z 476 (M+1⁺, 100%). Found: C, 58.31; H, 4.90; N, 2.94. Calcd.for C₂₃ H₂₃ F₆ NO₃ : 58.11; H, 4.88; N, 2.95%.

DESCRIPTION 5:(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(cyanomethyl)-2-phenylpiperidiniumhydrochloride

The compound of Description 1 (5 g), potassium carbonate (1.7 g) andbromoacetonitrile (0.87 ml) were suspended in dimethylformamide (15 ml)and the mixture was stirred under nitrogen at 60° C. for 3 h. Themixture was cooled, diluted with water (200 ml) and extracted with ethylacetate (2×50 ml). The organic extracts were washed with brine, dried(MgSO₄) and evaporated, affording a brown oil. This was purified onsilica using ethyl acetate in petrol (10%) as eluant. This afforded theproduct as a colourless oil. The hydrochloride salt was prepared bydissolution in ethereal hydrogen chloride and the salt wasrecrystallised from ether-hexane: mp 133°-134° C. ¹ H NMR (360 MHz,CDCl₃) d 1.75 (2H, mc, CHH), 1.90 (2H, me, CHH), 2.31 (1H, mc, CHH),2.71 (1H, mc, CHH), 3.19 (1H, mc, CHHN), 3.72 (1H, mc, CHHN), 3.81 (1H,d, J=17.5 Hz, NCHHCN), 3.86 (1H, s, CHO), 4.02 (1H, d, J=17.5 Hz,NCHHCN), 4.09 (1H, s, CHPh), 4.35 (1H, d, J=13.0 Hz, OCHH), 4.73 (1H, d,J=13.0 Hz, OCHH), 7.4 (3 H, mc, ArH), 7.69-7.73 (5H, m, ArH); MS (CI⁺)m/z 443 (M⁺ +1, 30%). Found: C, 54.87; H, 4.30; N, 5.66. Calcd. for C₂₂H₁₈ F₆ N₂ O.HCl: C, 55.18; H, 4.42; N, 5.85%.

DESCRIPTION 6:(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(thiocarboxamidomethyl)piperidine

The compound of Description 5 (1 g) was dissolved in dimethylformamide(anhydrous, 10 ml) and the solution was saturated with dry hydrogenchloride gas. The reaction was heated to 100° C. under nitrogen andthioacetamide (0.34 g) was added; this mixture was allowed to stir at100° C. for 3 h. Dimethylformamide was removed in vacuo. The residue wasextracted with ethyl acetate and the organic layer was washed withaqueous sodium bicarbonate, brine, dried (MgSO₄) and concentrated invacuo to afford a brown oil. This was purified on silica using agradient elution of ethyl acetate in petrol (10-50%). The product wasfurther purified by recrystallisation from ethyl acetate-petrol: mp164°-166° C.; ¹ H NMR (360 MHz, CDCl₃) d 1.56-1.70 (2H, m, CH₂),1.96-2.10 (1H, m, CHH), 2.15-2.32 (2H, m, CHHN+CHH), 2.98-3.06 (1H, bd,NCHH), 3.09 (1 H, d, J=18.0 Hz, CHHSNH₂), 3.50 (1H, d, J=18.0 Hz,NCHHCSNH₂), 3.50 (1H, s, CHO), 3.60 (1H, s, NCHPh), 4.04 (1H, d, J=12.0Hz, OCHHAr), 4.47 (1H, d, J=12.0 Hz, OCHHAr), 7.26-7.36 (5H, m, CHPh),7.53 (2H, s, Ar--H), 7.75 (H, s, Ar--H), 7.61 (1H, bs, NHH), 8.99 (1H,bs, NHH); MS (CI⁺) m/z 477 (M⁺ +1, 15%); Found: C, 55.09; H, 4.58; N,5.97. Calc for C₂₂ H₂₂ F₆ N₂ OS: C, 55.46; H, 4.65; N, 5.88.

DESCRIPTION 7:(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(carboxyhydrazidomethyl)-2-phenylpiperidiniumhydrochloride

Hydrazine hydrate (3.0 ml) was added to a solution of the compound ofDescription 2 (2.95 g) in ethanol (80 ml). The solution was heated atreflux for 18 h after which the ethanol was removed in vacuo. Theresidue was extracted into ethyl acetate and the organic layer waswashed with brine, dried (MgSO₄) and concentrated to give the titlecompound (2.79 g). This was dissolved in methanol (5 ml) and amethanolic solution of hydrogen chloride was added. Methanol was removedin vacuo and the salt was recrystallised from diethyl ether to give thehydrochloride salt. ¹ H NMR (360 MHz, DMSO) d 1.77-1.93 (2H, m, CH₂),2.08-2.21 (1H, m, CH₂), 2.22-2.35 (1H, m, CH₂), 3.56 (1H, d, NCHHCH₂),3.64 (1H, d, J=16.5 Hz, NCHHCO), 3.77 (1H, d, NCHHCH₂), 3.92 (1H, d,J=16.5 Hz, NCHHCO), 3.96 (1H, brs, CHO), 4.37 (1H, d, J=13.0 Hz, OCHH),4.83 (1H, d, J=13.0 Hz, OCHH), 4.95 (1H, s, CHPh), 7.36-7.46 (3H, m,ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (1H, s, ArH); MS(CI)⁺ m/z 475.

DESCRIPTION 6:(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(carboxyhydrazidomethyl)-2-phenylpiperidiniumhydrochloride

The title compound was prepared according to the procedure outlined inDescription 7 using the compound of Description 4 as a startingmaterial. ¹ H NMR (360 MHz, DMSO) d 1.77-1.93 (2H, m, CH₂), 2.08-2.21(1H, m, CH₂), 2.22-2.35 (1H, m, CH₂), 3.56 (1H, d, NCHHCH₂), 3.64 (1H,d, J=16.5 Hz, NCHHCO), 3.77 (1H, d, NCHHCH₂), 3.92 (1H, d, J=16.5 Hz, ⁻NCHHCO), 3.96 (1H, brs, CHO), 4.37 (1H, d, J=13.0 Hz, OCHH), 4.83 (1H,d, J=13.0 Hz, OCHH), 4.95 (1H, s, CHPh), 7.36-7.46 (3H, m, ArH),7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (1 H, s, ArH); MS(CI)⁺ m/z 475.

DESCRIPTION 9:(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(cyanomethyl)-2-phenylpiperidine

The title compound was prepared from the reaction of bromoacetonitrileand the compound of Description 3 according to the procedure detailed inDescription 5. Purification by chromatography on silica using 10% hexanein ethyl acetate afforded the product as a colourless oil. ¹ H NMR (360MHz, CDCl₃) d 1.75 (2H, mc, CH₂ CH₂ N), 2.14 (2H, mc, CH₂ CH₂ N),2.63-2.74 (1H, m, CHHN), 2.96-3.06 (1H, m, CHHN), 3.35 (1H, d, J=17.0Hz, CHHCN), 3.48 (1H, d, J=2.0 Hz, CHO), 3.55 (1H, d, J=17.0 Hz, CHHN),3.64 (1H, d, J=2.0 Hz, CHPh), 4.07 (1H, d, J=12.0 Hz, OCHH), 4.52 (1H,d, J=12.0 Hz, OCHH), 7.28-7.38 (3H, m, ArH), 7.4-7.48 (2H, m, ArH), 7.56(2H, m ArH), 7.73 (1H, m, ArH).

DESCRIPTION 10:(2S,3S)-3-((3-t-Butyl-5-methylphenyl)methyloxy)-2-phenylpiperidine

This compound was prepared from the compound of Description 3c and3-t-butyl-5-methylbenzyl bromide, following the procedure described inDescriptions 1c-e. mp 180°-182° C. MS (CI⁺) m/z 338 (M⁺ +1, 100%).Found: C, 73.81; H, 8.63; N, 3.74. Calcd. for C₂₃ H₃₁ NO.HCl: C, 73.87;H, 8.62; N, 3.75%.

DESCRIPTION 11:(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidine

This compound was prepared from the compound of Description 3c and3,5-dichlorobenzyl chloride, following the procedure described inDescriptions 1c-e. ¹ H NMR (CDCl₃) δ1.49-1.53 (1H, m, CHH), 1.60-1.70(1H, m, CHH), 1.82-1.95 (1H, m, CHH), 2.14-2.18 (1H, m, CHH), 2.79-2.87(1H, m, NCHH), 3.27-3.31 (1H, m, NCHH), 3.60 (1H, s, CHO), 3.82 (1H, s,CHPh), 4.02-4.05 (1H, d, J=13 Hz, OCHH), 4.31-4.35 (1H, d, J=13 Hz,OCHH), 6.80 (2H, s, ArH), 7.15 (1H, s, ArH), 7.25-7.35 (5H, m, ArH).Found: C, 58.24; H, 5.38; N, 3.91. Calcd. for C₁₈ H₁₉ Cl₂ NO.HCl: C,58.01; H, 5:41; N, 3.76%.

DESCRIPTION 12:(2S,3S)-3-((3-Chloro-5-methylphenyl)methyloxy)-2-phenylpiperidine

This compound was prepared from the compound of Description 3c and3-chloro-5-methylbenzyl bromide, following the procedure described inDescriptions 1c-e: mp 235°-237° C. MS (CI⁺) m/z 316 (M⁺ +H, 100%).Found: C, 64.68; H, 6.50; N, 3.98. Calcd. for C₁₉ H₂₂ ClNO.HCl: C,64.78; H, 6.58; N, 3.98%.

DESCRIPTION 13:(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(diphenylmethyl)pyrimidiniumhydrochloride

(a) N-t-Butyloxycarbonyl-(S)-diphenylalanal

A solution of methyl sulfoxide (4.4 ml) in dichloromethane (13 ml) wasadded dropwise to a cooled (-78° C.) solution of oxalyl chloride (4 ml)in dichloromethane (50 ml). After 15 min, a solution ofN-t-butyloxycarbonyl-(S)-diphenylalanol (10 g) in dichloromethane (150ml) was added dropwise at -30° C. The solution was allowed to stir for30 min, triethylamine (17 ml) was added and the solution was allowed towarm to -10° C. Ice-water (200 ml) was added to the solution which wasthen poured onto hexane (600 ml). The organic phase was separated,washed successively with citric add (200 ml), saturated aqueous sodiumbicarbonate (2×150 ml), brine (1×150 ml) then dried (MgSO₄) andconcentrated in vacuo to leave a white crystalline solid. ¹ H NMR (250MHz, CDCl₃) δ1.42 (9H, s, C(CH₃)₃), 4.48 (1H, d), 4.86 (1H, d), 5.10(1H, t), 7.26 (10H, m, ArH), 9.6 (1H, s, CHO).

(b)N-t-Butyloxycarbonyl-1-(diphenylmethyl)-2-hydroxy-pent-4-enyl-1-amine

A solution of N-t-butyloxycarbonyl-(S)-diphenylalanal (10.9 g) intetrahydrofuran (60 ml) was added dropwise to a solution of allylmagnesium chloride (2M in tetrahydrofuran, 36 ml) at -10° C. After 30min the mixture was poured onto ice-cold saturated aqueous ammoniumchloride and the resulting mixture was extracted with ethyl acetate(3×150 ml). The combined organic extracts were washed with brine (1×100ml), then dried (MgSO₄) and concentrated in vacuo. The residue waspurified by chromatography on silica gel using hexane in ethyl acetate(gradient elution of 9:1 to 4:1) as eluant to afford the compound as awhite solid. ¹ H NMR (360 MHz, CDCl₃) δ1.42 (9H, s, (CH₃)₃), 2.22 (2H,m), 2.68 (3H, brs), 3.48 (t), 3.57 (1H, m), 3.86 (1H, s), 4.07 (d, J=11Hz), 5.04 (1H, m), 5.71 (1H, m), 6.97-7.36 (10H, m, ArH).

(c)2-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-N-t-butyloxycarbonyl-1-(diphenylmethyl)-pent-4-enyl-1-amine

Sodium hydride (80% in oil, 0.53 g) was added to a solution of3,5-bis(trifluoromethyl)benzyl bromide (5 ml) and the compound of (13b)above (5 g) in dimethylformamide (8 ml). After stirring for 1 h water(80 ml) was added and the mixture was extracted with ethyl acetate(3×100 ml). The combined organics extracts were washed with brine (1×100ml) then dried (MgSO₄) and concentrated to leave an oil which waspurified on silica using hexane in ethyl acetate as eluant (gradientelution of 97:3 to 4:1). This afforded the title compound as acolourless oil. ¹ H NMR (360 MHz, CDCl₃) δ1.25 (s), 1.30 (s), 2.35 (m),3.31 (m), 3.40 (dd, J=5.2, 8.3 Hz), 3.97 (d), 4.27 (d), 4.38 (m), 4.65(m), 4.85 (d), 5.16-5.02 (m), 5.77 (m), 7.35-7.13 (m), 7.76 (s), 7.85(s).

(d)(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-2-(diphenylmethyl)pyrrolidiniumhydrochloride

A solution of the compound of (c) above (5.2 g) in dichloromethane (40ml) and methanol (40 ml) was treated with a stream of ozone in oxygen at-78° C. for 1 h. Methyl sulfide (3 ml) was added and the mixture waswarmed to 23° C. and concentrated in vacuo. The residue was dissolved inchloroform (50 ml), triethylsilane (5.6 ml) was added followed bydropwise addition of a solution of trifluoroacetic acid (6.9 ml) inchloroform (5 ml). After 1 h the solvent was evaporated in vacuo andtrifluoroacetic acid (10 ml) was added to the residue. After stirringfor 30 min the mixture was concentrated in vacuo and the residue waspartitioned between dichloromethane and saturated aqueous sodiumbicarbonate. The organic layer was dried (K₂ CO₃) and concentrated toleave a brown oil. This was purified on silica gel eluting withdichloromethane/methanol (99:1) to provide the title compound as thefree base. This was converted to the salt by treatment with methanolichydrogen chloride: mp >230° C. [α]²³ _(D) =+46.6° (c=1, CH₃ OH). Found:C, 59.95; H, 4.74; N, 2.63%. Calcd. for C₂₆ H₂₃ F₆ NO.HCl.0.2H₂ O: C,60.11; H, 4.73; N, 2.70%.

DESCRIPTION 14:(2R,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(diphenylmethyl)pyrrolidiniumhydrochloride

The title compound was prepared fromN-t-butyloxycarbonyl-(R)-diphenylalanol by a procedure analagous to thatdescribed in Description 13: mp>230° C. [α]²³ _(D) =+12.1° (c=1, CH₃OH).

DESCRIPTION 15: (2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-(diphenylmethyl)pyrrolidinium hydrochloride

(a)N-t-Butyloxycarbonyl-2-((3,5-dichlorophenyl)methyloxy-1-(diphenylmethyl)pent-4-enyl-1-amine

The compound of Description 13b was alkylated with 3,5-dichlorobenzylchloride by a procedure analagous to that described in Description 13c,to afford the title compound as an oil. ¹ H NMR (360 MHz, CDCl₃) δ1.25(9H, s), 2.41-2.27 (2H, m), 3.32 (1H, m), 4.07 (1H, d, J=11 Hz), 4.13(1H, d, J=12 Hz), 4.30 (1H, d, J=12 Hz), 4.65 (2H, m), 5.13 (2H, m),5.76 (1H, m), 7.35-6.60 (13H, m). MS (CI⁺) m/z 526, 528 (M⁺ +1, 100%,80%).

(b)(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-(diphenylmethyl)pyrrolidiniumhydrochloride

The compound of Description 15a above was treated with ozone followed bytriethylsilane-trifluoroacetic acid by a procedure analagous to thatdescribed in Description 13d to afford the title compound as a whitecrystalline solid: mp>230° C. Found: C, 64.52; H, 5.34; N, 3.12. Calcd.for C₂₄ H₂₃ Cl₂ NO.HCl: C, 64.23; H, 5.39; N, 3.12%.

DESCRIPTION 16:(2S,3S)-3-((3-t-Butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidiniumhydrochloride

(a) 4-t-Butyl-2-chloro-6-(methylthiomethyl)aniline.

4-t-Butyl-2-chloroaniline (30 g) was dissolved in dichloromethane (1.2l) and the solution was cooled to -5° C. N-chlorosuccinimide (21.7 g)was added portionwise to the vigorously stirred solution and stirringwas continued for 1 h. Dimethyl sulfide (35 ml) was added to thesolution (-5° C.) and stirring was continued for a further 1 h. Thesolution was then cooled to -65° C. and triethylamine (27 ml) was added.This solution was allowed to warm to room temperature overnight. Thesolution was evaporated to half volume, washed with sodium hydroxide(1N), water and brine successively. The organic solution was dried andevaporated and the residue was purified on silica using hexane to 3%ether in hexane as eluant. This afforded the product (31.2 g) as a redoil. ¹ H NMR (CDCl₃, 250 MHz) δ1.27 (9H, s, (CH₃)₃), 1.99 (3H, s, SCH₃),3.69 (2H, s, CH₂ SCH₃), 4.38 (2H, br s, NH₂), 6.92 (1H, d, J=2.0 Hz,ArH), 7.21 (1H, d, J=2.0 Hz, ArH). MS (CI⁺) m/z 244 (M⁺ +1, 100%).

(b) 4-t-Butyl-2-chloro-6-methylaniline

4-t-Butyl-2-chloro-6-(methylthiomethyl)aniline (1.3 g) was dissolved inmethanol (50 ml) and Raney nickel (prewashed to pH 7) was addedportionwise until t.l.c. indicated all starting material had reacted(ether-hexane, 1:10). The Raney nickel was removed by filtration throughcelite and the filtrate was evaporated. The residue was dissolved inether and washed with brine, dried (MgSO₄) and evaporated. The residuewas purified on silica using hexane--5% ether in hexane as eluant toafford the product as a yellow liquid. ¹ H NMR (360 MHz, CDCl₃) δ1.26(9H, s, (CH₃)₃), 2.19 (3H, s, CH₃), 3.97 (2H, s, NH₂), 6.97 (1H, d,J=2.0 Hz, ArH), 7.14 (1H, d, J=2.0 Hz, ArH).

(c) 3-t-Butyl-5-chlorotoluene

4-t-Butyl-2-chloro-6-methylaniline (1.97 g) was dissolved in ethanol (50ml); sulphuric acid (1.88 ml, conc.) was added dropwise and theresulting blue solution was heated at reflux. Sodium nitrite (1.72 g)was added portionwise over 30 min. The resulting mixture was heated atreflux for a further 30 min, then cooled and was poured onto ice-waterand extracted with ether (2×50 ml). The ethereal extract was dried(MgSO₄) and evaporated and the residue was purified on silica gel usinghexane as eluant. This afforded the product as a colourless oil. ¹ H NMR(360 MHz, CDCl₃) δ1.29 (9H, s, (CH₃)₃), 2.31 (3H, s, CH₃), 6.98 (1H,brs, ArH), 7.05 (1H, brs, ArH), 7.15 (1H, brs, ArH). MS (CI⁻) m/z 181(M⁺ -H, 100%).

(d) 3-t-Butyl-5-chlorobenzyl bromide

3-t-Butyl-5-chlorotoluene (5.7 g) was dissolved in carbon tetrachloride(80 ml) and N-bromosuccinimide (5.56 g) was added followed by benzoylperoxide (750 mg). This mixture was heated at reflux for 6h. The mixturewas cooled, filtered through celite and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica using hexaneas eluant. This afforded the title compound as a colourless liquid. ¹ HNMR (360 MHz, CDCl₃) δ1.31 (9H, s, (CH₃)₃), 4.42 (2H, s, CH₂), 7.20 (1H,t, J=1.5 Hz, ArH), 7.26 (1H, t, J=1.5 Hz, ArH), 7.28 (1H, t, J=1.5 Hz,ArH).

(e)(2S,3S)-1-t-Butyloxycarbonyl-3-((3-t-butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidine.

(+)-cis-3-Hydroxy-2-phenylpiperidine (Description 3c) was reacted with3-t-butyl-5-chlorobenzyl bromide (Description 15d above) according tothe procedure detailed in Description 1c-d to afford the title compound.¹ H NMR (360 MHz, CDCl₃) δ1.27 (9H, s, C(CH₃)₃), 1.46 (9H, s, C(CH₃)₃),1.52-1.66 (2H, m), 1.8-2.0 (2H, m), 2.69 (1H, td, J=3.5 Hz, 13.0 Hz,NCHH), 3.81 (1H, q, J=5 Hz, NCHH), 3.92 (1H, brd, CHO), 4.60 (2H, q,J=12 Hz, OCH₂), 5.70 (1H, brs, CHPh), 7.10 (1H, s, ArH), 7.18 (1H, s,ArH), 7.22 (2H, s, ArH), 7.43-7.47 (2H, m, ArH), 7.57-7.59 (2H, m, ArH).

(f) The compound of Description 15e above was dissolved in methanolichydrogen chloride overnight. The solution was then concentrated in vacuoand the residue triturated with ether. This afforded the title compoundas a white crystalline powder: mp 210°-211° C. ¹ H NMR (⁻ 360 MHz,DMSO-d₆) δ1.21 (9H, s, C(CH₃)₃), 1.66-1.80 (2H, m, CH₂), 1.86-1.93 (1H,m, CHH), 2.18-2.22 (1H, m, CHH), 3.04-3.11 (1H, m, NCHH), 3.3 (1H, m,NCHH), 3.88 (1H, brs, CHO), 4.14 (1H, d, J=12 Hz, OCHH), 4.52 (1H, s,CHPh), 4.53 (1H, d, J=12 Hz, OCHH), 6.95 (1H, s, ArH), 7.00 (1H, s,ArH), 7.24 (1H, t, J=1.8 Hz, ArH), 7.3-7.5 (5H, m, ArH), MS (CI⁺) m/z358 (M⁺ +1, 100%). Found: C, 66.68; H, 7.29; N, 3.40. Calcd. for C₂₂ H₂₈ClNO.HCl: C, 67.00; H, 7.41; N, 3.55%.

DESCRIPTION 17:(2R*,3R*)-3-((3-Carbomethoxyphenyl)methyloxy)-2-phenylpiperidine

(a)(2R*,3R*)-1-t-Butyloxycarbonyl-3-((3-cyanophenyl)methyloxy)-2-phenylpiperidine

This compound was prepared from1-t-butyloxycarbonyl-3-hydroxy-2-phenylpiperidine (Description 1c) andα-bromo-m-tolunitrile according to the procedure described in Example1d. ¹ H NMR (360 MHz, CDCl₃) δ1.49 (9H,s, (CH₃)₃), 1.6-1.72 (2H, m),1.87-1.99 (2H, m), 2.72 (1H, dt, J=13, 4 Hz, NCHH), 3.80-3.95 (2H, m,CHO+NCHH), 4.65 (2H, q, J=12 Hz, OCH₂), 5.69 (1H, brs, CHPh), 7.1-7.5(9H, m, ArH).

(b) (2R*,3R*)-3-((3-Carbomethoxyphenyl)methyloxy-2-phenylpiperidine

The compound of (a) above (1.5 g) was dissolved in methanol (15 ml) andconcentrated hydrochloric acid (aqueous, 10 ml) was added. The contentswere heated at reflux for 12 h. The solution was cooled and evaporatedto leave a brown oil. This was dissolved in methanolic hydrogen chlorideand the resulting solution was stirred overnight, then evaporated. Theresidue was purified by dispersion between water and ethyl acetate andthe organic layer was dried (MgSO₄) and concentrated. The residue waspurified by chromatography on silica using a gradient elution of 2%-6%methanol in dichloromethane. The first compound to elute wascharacterised as the hydrochloride salt by dissolution in methanolichydrogen chloride. The salt was recrystallised from ethyl acetatemethanol: mp 206°-208° C.

(c) (2R*,3R*)-3-((3-(Carbomethoxy)phenyl)methyloxy)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.45-1.71 (2H, m, NCH₂ CH₂ CH₂), 1.83-2.02 (1H, m, NCH₂CHH), 2.12-2.23 (1H, m, NCH₂ CHH), 2.44 (1H, bs, NH), 2.77-2.90 (1H, m,NCHH), 3.24-3.34 (1H, m, NCHH), 3.61-3.66 (1H, bs, CHO), 3.8-3.83 (1H,d, J=15 Hz, CHPh), 3.90 (3H, s, COOCH₃), 4.15 (1H, d, J=12 Hz, OCHH),4.39 (1H, d, J=12 Hz, OCHH), 7.09 (7H, m, ArH), 7.71 (1H, bs, ArH),7.83-7.89 (1H, m, ArH); MS (CI⁺) m/z 326 (M⁺ +1, 100%). Found: C, 66.31;H, 6.36; N, 3.80. Calcd. for C₂₀ H₂₃ NO₃.HCl: C, 66.38; H, 6.69; N,3.87%.

DESCRIPTION 18:(2R*,3R*)-3-((3-Carboxamidophenyl)methyloxy)-2-phenylpiperidine

The second compound to elute from the column described in 17b above wasisolated as a colourless oil. ¹ H NMR (360 MHz, CDCl₃) δ1.2-2.2 (4H, m),2.82 (1H, mc), 3.27 (1H, mc), 3.66 (1H, s), 3.82 (1H, s), 4.16 (1H, d,J=12 Hz, OCHH), 4.48 (1H, d, J=12 Hz, OCHH), 5.53 (1H, brs, CONHH), 6.18(1H, brs, CONHH), 7.0-7.4 (9H, m, ArH).

DESCRIPTION 19:(2R*,3R*)-3-((2-Methoxy-3-nitrophenyl)methyloxy)-2-phenylpiperidiniumhydrochloride

This compound was prepared from the compound of Description 1c and2-methoxy-5-nitrobenzyl bromide, following the procedure described inDescriptions 1c-e. mp 246°-248° C. MS (CI⁺) m/z 343 (M⁺ +1, 45%). Found:C, 60.52; H, 5.96; N, 7.45. Calcd. for C₁₉ H₂₂ N₂ O₄.HCl: C, 60.24; H,6.12; N, 7.39%.

DESCRIPTION 20:(2R*,3R*)-3-((5-Amino-2-methoxyphenyl)methyloxy)-2-phenylpiperidiniumhydrochloride

The compound of Description 19 (0.342 g) was dissolved in methanol (20ml) with hydrochloric acid (1 ml, 2N). Palladium on charcoal (50 mg) wasadded and the mixture placed under an atmosphere of hydrogen for 1 h atroom temperature. The solvent was removed in vacuo and the residuebasified with sodium hydroxide (2M). This solution was extracted withethyl acetate and the organic extracts were dried (MgSO₄) andconcentrated to leave a brown oil; this was purified by columnchromatography on silica using 8% methanol in dichloromethane as eluent.The resulting oil was characterised as the salt prepared by treatmentwith methanolic hydrogen chloride: mp 241°-243° C.

The following piperidines were prepared according to the proceduresoutlined in Descriptions 1 and 3, using the appropriate benzyl halide.

DESCRIPTION 21:(2S,3S)-2-Phenyl-3-((3-(trifluoromethyl)phenyl)methyloxy)piperidine

¹ H NMR (CDCl₃) δ1.4-2.2 (4H, m), 2.45 (1H, brs), 2.83 (1H, td, J=13 Hzand 4 Hz), 3.3 (1H, m), 3.64 (1H, d, J=2 Hz), 3.82 (1H, d, J=2 Hz), 4.13(1H, d, J=12 Hz, OCHH), 4.42 (2H, J=12 Hz, OCHH), 7.75 (m, 9H, ArH).

DESCRIPTION 22:(2S,3S)-3-((3,4-Dichlorophenyl)methyloxy)-2-phenylpiperidiniumhydrochloride

¹ H NMR (DMSO-d₆), 1.65-1.8 (2H, m), 1.8 (1H, m), 2.16 (1H, d, J=12 Hz),3.05 (1H, m), 3.25 (1H, m), 3.83 (1H, s), 4.12 (1H, d, J=12 Hz), 4.5(2H, m), 7.05 (1H, dd, J=7 & 2 Hz), 7.28 (1H, d, J=2 Hz), 7.35-7.5 (6H,m), 9.05 (1H, br s), 9.8 (1H, br s).

DESCRIPTION 23:(2S,3S)-3-((2,3-Dimethylphenyl)methyloxy)-2-phenylpiperidiniumhydrochloride.

Ethyl acetate (10 ml) was saturated with hydrogen chloride by passingHCl gas for 5 min and a solution of 0.254 g of(2S,3S)-1-t-butoxycarbonyl-3-((2,3-dimethylphenyl)methoxy)-2-phenylpiperidine(prepared according to Description 3d) in 7 ml of ethyl acetate wasadded. After stirring for 2 h, the reaction mixture was concentrated invacuo. The residual white solid was washed with ether, filtered anddried to obtain 0.23 g of(2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidiniumhydrochloride. ¹ H NMR (DMSO-d₆) δ1.6-1.9 (3H, m), 1.75 (3H, s), 2.15(3H, s), 2.2 (1H, m), 3.05 (1H, m), 3.25 (1H, m), 3.84 (1H, s), 4.05(1H, d, J=14 Hz), 4.45 (1H, d, J=14 Hz), 4.48 (1H, s), 6.95-7.5 (8H, m),8.8 (1H, br s), 9.4 (1H, br s).

DESCRIPTION 24:(2S,3S)-3-((3-t-Butylphenyl)methyloxy)-2-phenylpiperidiniumhydrochloride

¹ H NMR (360 MHz, CDCl₃) δ1.21 (9H, s, C(CH₃)₃), 1.45 (3H, s), 1.52-1.67(2H, m, CH₂), 2.04-2.12 (1H, m, CHH), 2.30-2.34 (1H, m, CHH), 2.93-2.96(1H, m, NCHH), 3.54 (1H, d, J=13 Hz, NCHH), 3.72 (1H, s, NCHCHO), 4.14(1H, d, J=2 Hz, NCHCHO), 4.28-4.36 (2H, q, J=13 Hz, OCHH), 6.87-6.89(1H, m, ArH), 7.05 (1H, s, ArH), 7.11-7.15 (1H, m, ArH), 7.20-7.34 (4H,m, ArH), 7.55-7.58 (2H, m, ArH). MS (CI+) m/z 323 (M⁺ +1, 100%).

DESCRIPTION 25:(2R*,3R*)-3-((3,5-Dimethylphenyl)methyloxy)-2-phenylpiperidiniumhydrochloride

¹ H NMR (360 MHz, CDCl₃) δ1.48 (m), 1.62 (m), 1.86 (m), 2.20 (s), 2.82(ddd, J=3.0. 3.0, 12.6 Hz), 3.26 (dt, J=2.15, 2.15, 12.5 Hz), 3.63 (s),3.78 (s), 4.10 (d, J=12.0 Hz), 4.33 (d, J=12.0 Hz), 6.31 (s), 7.2-7.4(m). MS (CI⁺) m/z 296 (M⁺ +1).

DESCRIPTION 26:(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl)piperidine

(a) Methyl-4-nitrobutyrate and 3-chlorobenzaldehyde were reacted in ananalogous manner to that described in Description 1a to give2-(3-chlorophenyl)-3-nitro-6-oxopiperidine: mp 131°-133° C. ¹ H NMR (360MHz, CDCl₃) δ2.26-2.36 (1H, m), 2.50-2.72 (3H, m), 4.66-4.71 (1H, m),5.24-5.28 (1H, d), 6.57 (1H, s), 7.17-7.40 (4H, m).

(b) The product of part a) was treated analogously to that described inDescription 1b to give 2-(3-chlorophenyl)-3,6-dioxopiperidine: mp144°-147° C. ¹ H NMR (360 MHz, CDCl₃) δ2.8 (4H, m), 5.0 (1H, d), 6.4(1H, s), 7.22-7.42 (4H, m).

c) The product of part b) was treated analogously to that described inDescription 1c and 3a to give cis-2-(3-chlorophenyl)-3-hydroxypiperidinetosylate salt: mp >250° C. ¹ H NMR (360 MHz, CDCl₃) δ1.60-2.07 (4H, m),2.28 (3H, s), 3.00-3.11 (1H, m), 4.02 (1H, s), 4.62-4.66 (1H, d), 5.96(1H, s), 7.10-7.20 (2H, d), 7.41-7.59 (6H, m).

d) The product of part c) was treated analogously to that described inDescription 1c to givecis-1-t-butyloxycarbonyl-2-(3-chlorophenyl)-3-hydroxypiperidine as aclear, viscous oil. ¹ H NMR (360 MHz, CDCl₃) δ1.40 (9H, s), 1.61-1.90(4H, m), 2.88-3.01 (1H, ddd), 3.93-3.99 (1H, dd), 4.03-4.10 (1H, m),5.33 (1H, d), 7.20-7.26 (2H, m), 7.34-7.38 (1H, m), 7.47-7.52 (1H, m).m/z (CI⁻) 310, 312; m/z (CI⁺) 312, 314.

e) The product of part d) and 3,5-bis(trifluoromethyl)benzylbromide weretreated in an analogous manner to that described in Description 1d togivecis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-1-t-butyloxy-carbonyl-2-(3-chlorophenyl)piperidine.¹ H NMR (250 MHz, CDCl₃) δ1.24-1.30 (1H, m), 1.47 (9H, s), 1.60-2.00(3H, m), 2.67-2.80 (1H, ddd), 3.81-4.01 (2H, m), 4.8 (2H, s), 5.61-5.67(1H, d), 7.23-7.27 (2H, m), 7.39-7.44 (1H, m), 7.6 (1H, s), 7.78 (2H,s), 7.8 (1H, s).

f) The product of part e) was treated in an analogous manner to thatdescribed in Description 1e to givecis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl)piperidinehydrochloride salt, mp=158° C. ¹ H NMR (360 MHz, DMSO-d₆) δ1.70-1.96(4H, m), 2.19-2.28 (1H, m), 3.02-3.13 (1H, m), 3.84 (1H, s), 4.35-4.39(2H, d), 4.60 (1H, s), 4.79-4.85 (2H, d), 7.39-7.44 (3H, m), 7.58 (1H,s), 7.84 (2H, s), 7.97 (1H, s), 9.2 (br s), 10.05 (br s). Found: C,50.44; H, 4.13; N, 3.01. C₂₀ H₁₈ ClF₆ NO.HCl requires C, 50.65; H, 4.04;N, 2.95%. m/z (CI⁺), 438,440.

DESCRIPTION 27:2S,3S)-3-((3-Fluoro-5-methylphenyl)methyloxy)-2-phenylpiperidine

mp 219°-221° C. ¹ H NMR (360 MHz, CDCl₃) δ1.50-1.68 (2H, m), 2.11-2.15(1H, m), 2.20 (3H, s, CH₃), 2.31-2.35 (1H, m), 2.94-2.98 (1H, m, NCHH),3.55-3.58 (1H, d, J=12 Hz, NCHH), 3.69 (1H, bs, CHO), 4.15-4.18 (1H, m,CHPh), 4.18 (1H, d, J=13 Hz, OCHH), 4.33 (1H, d, J=13 Hz, OCHH), 6.47(1H, d, ArH), 6.59 (1H, s, ArH), 6.66 (1H, d, ArH), 7.26-7.37 (3H, m,ArH), 7.52-7.54 (2H, m, ArH). MS (CI⁺) m/z 300 (M⁺ +1, 100%).

DESCRIPTION 28:(3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-methyl-2-(2R*)-2-phenylpiperidine

(a) 3,6-Dioxo-2-phenylpiperidine (Description 1b)(5 g) was dissolved indimethylformamide (25 ml) at 0° C. Sodium hydride (873 mg, 80%dispersion in oil) was added portionwise and the mixture stirred for 15min. Methyl iodide was added (1.8 ml) and the mixture was stirred for 12h. The mixture was diluted with water (250 ml) and extracted with ethylacetate (3×). The combined organic extracts were washed with brine,dried (MgSO₄) and concentrated to leave a solid:3,6-dioxo-2-methyl-2-phenylpiperidine.

(b) The ketone of (a) above (3.2 g) was suspended in methanol undernitrogen and the temperature brought to -40° C. Sodium borohydride (0.3g) was added portionwise. The mixture was stirred for 30 min and thenconcentrated in vacuo, azeotroping with tetrahydrofuran. Boranetetrahydrofuran complex (64 ml, 1.0M in tetrahydrofuran) was added andthe mixture was heated at reflux overnight. The mixture was cooled andquenched carefully with methanol, and the mixture was then concentratedin vacuo. The resulting residue was dissolved in ethanol (100 ml) andpotassium carbonate (4.2 g) was added. The mixture was heated at refluxfor 12 h. The mixture was cooled and evaporated and the residue wasextracted with ethyl acetate and water. The organic extract was washedwith brine, dried (MgSO₄) and evaporated to afford3-hydroxy-2-methyl-2-phenylpiperidine as a white solid. ¹ H NMR (360MHz, CDCl₃) δ7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m,ArH), 3.89 (1H, mc), 2.89-3.01 (2H, m), 1.67-1.91 (4H, m), 1.39 (3H, s,CH₃).

(c) The alcohol of (b) above (3 g) was dissolved in dichloromethane (50ml) and di-t-butyldicarbonate (3.48 g) was added. The solution wasallowed to stir for 12 h. The solution was concentrated in vacuo and theresidue was purified by chromatography on silica using ethyl acetate inpetrol (20:80) as eluent. This affordedN-t-butyloxycarbonyl-2-hydroxy-2-methyl-2-phenylpiperidine as a clearoil. ¹ H NMR (250 MHz, CDCl₃) δ1.08 (9H,s, (CH₃)₃), 1.80 (3H, s, CH₃),1.6-2.0 (4H, m), 3.6-3.74 (2H, m), 3.8-3.92 (1H, m, CHO), 7.2-7.36 (5H,m, ArH).

(d) The alcohol of (c) above (2.2 g) was dissolved in drydimethylformamide (12 ml). Sodium hydride was added (0.36 g, 60%dispersion in oil) portionwise and the mixture was allowed to stir atroom temperature for 30 min. 3,5-Bis(trifluoromethyl)benzyl bromide (3.5g) was added dropwise and the mixture was allowed to stir for 5 h. Themixture was diluted with aqueous ammonium chloride, extracted with ethylacetate and the organic extract was washed with brine, dried (MgSO₄) andevaporated in vacuo. The residue as purified by column chromatography onsilica using a gradient elution, 100% petrol to 10% ethyl acetate inpetrol as eluant, to afford the product3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-1-t-butyloxycarbonyl-2-methyl-2-phenylpiperidineas a colourless oil. ¹ H NMR (360 MHz, CDCl₃) δ1.13 (9H, s (CH₃)₃), 1.85(3H, s, CH₃), 1.85-1.99 (4H, m, CH₂ CH₂), 3.48 (1H, brs, NCHH),3.68-3.75 (1H, m, NCHH), 3.80-3.85 (1H, m, CHO), 3.85 (1H, d, J=12 Hz,OCHH), 4.36 (1H, d, J=12 Hz, OCHH), 7.17-7.32 (5H, m, ArH), 7.42 (2H, s,ArH), 7.71 (1H, s, ArH).

(e) The compound of (d) above (2.1 g) was dissolved in trifluoroaceticacid (30 ml) for 10 min and was then evaporated in vacuo. The residuewas dissolved in dichloromethane, washed with sodium hydroxide (2M),water and brine, then dried (MgSO₄) and concentrated in vacuo.Methanolic hydrogen chloride was added to the residue and when dissolvedthe solvent was evaporated. The residue was triturated with ether toafford the product as a white powder:(3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-methyl-(2R*)-2-phenyl-piperidine.¹ H NMR (360 MHz, DMSO) δ1.67 (3H, s, CH₃), 1.70 (1H, m), 1.84-1.91 (1H,m), 1.99-2.06 (2H, m), 3.16 (1H, m), 3.33 (1H, m), 4.19 (1H, s), 4.29(1H, d, J=12 Hz, OCHH), 4.75 (1H, d, J=12 Hz, OCHH), 7.29-7.33 (1H, m,ArH), 7.37-7.41 (3H, m, ArH), 7.54 (2H, s, ArH), 7.56 (1H, brs, ArH),7.89 (1H, s, ArH). Found: C, 55.38; H, 4.92; N, 3.08 Calcd. for C₂₁ H₂₁F₆ NO: C, 55.58; H, 4.89; N, 3.09%.

DESCRIPTION 29:(2S,3S)-3-((3,4-Dimethylphenyl)methyloxy)-2-phenylpiperidine

¹ H NMR (CDCl₃) δ1.4-1.9 (3H, m), 2.11 (3H, s), 2.17 (3H, s), 2.1-2.3(1H, m), 2.78 (1H, m), 3.25 (1H, m), 3.60 (1H, s), 3.76 (1H, s), 4.08(1H, d, J=12 Hz), 4.27 (1H, d, J=12 Hz), 6.7 (2H, m), 6.92 (1H, d, J=9Hz), 7.2.-7.5 (5H, m).

DESCRIPTION 30:(2S,3S)-3-((3-(isoPropoxy)phenyl)methyloxy)-2-phenylpiperidine

¹ H NMR (250 MHz, CDCl₃) δ1.6-1.9 (3H, m), 1.97 (1H, d, J=7 Hz), 2.16(1H, m), 3.05 (1H, m), 3.3 (1H, m), 3.84 (1H, s), 4.09 (1H, d, J=12 Hz),4.41 (1H, d, J=12 Hz), 4.44 (1H, m), 4.5 (1H, s), 6.6 (2H, m), 6.72 (1H,m), 7.09 (1H, t, J=8 Hz), 7.3-7.5 (5H, m).

DESCRIPTION 31:(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(3-fluorophenyl)piperidine

¹ H NMR (360 MHz, CDCl₃) δ1.66-1.9 (3H, m), 2.2-2.3 (1H, m), 2.43-2.5(1H, m), 3.0-3.2 (1H, m), 3.98 (1H, s), 4.37 (1H, d, J=12 Hz), 4.62 (1H,s), 4.79 (1H, d, J=12 Hz), 7.04-7.46 (4H, m, ArH), 7.80 (2H, s, ArH),7.96 (1H, s, ArH).

EXAMPLE 1

3-Amino-5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-oxadiazole

Hydroxyguanidine sulphate hydrate (2.3 g) was dissolved in water andfreeze-dried overnight. Ethanol (35 ml) and powdered molecular sieves (1g) were added to the solid hydroxyguanidine and the suspension wasstirred under nitrogen for 1 hour. Sodium (670 mg) was added to themixture which was stirred until all sodium had reacted. The suspensionassumed an orange colour at this time and was placed in an ultrasoundbath for 15 min. The ester of Description 2 (1.4 g) was added to themixture which was then heated at reflux for 2 h. The reaction mixturewas cooled and filtered through celite. Ethanol was removed in vacuo andthe residue was extracted into ethyl acetate and washed with water andbrine. The organic layer was dried (MgSO₄) and evaporated. The residuewas purified on silica using 25% ethyl acetate in petrol as eluant. Thisafforded the product (800 mg) as a solid which was recrystallised fromether/hexane to afford colourless prisms: mp 160°-161° C. ¹ H NMR (360MHz, DMSO-d₆) d 1.47-1.54 (2H, m, CH₂), 1.85-1.9 (1H, m, CHH), 2.14-2.17(1H, m, CHH), 2.35-2.40 (1H, m, CHHN), 2.99-3.02 (1H, m, CHHN), 3.35(1H, d, J=15.0 Hz, N--CHH-oxadiazole), 3.60 (2H, brs, NCHCHO), 3.65 (1H,d, J=15.0 Hz, N--CHH-oxadiazole), 4.06 (1H, d, J=13.0 Hz, OCHH), 4.62(1H, d, J= 13.0 Hz, OCHH), 6.2 (2H, brs, NH₂), 7.23-7.31 (3H, m, ArH),7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI⁺)m/z 501 ((M+1)⁺, 75%). Found: C, 54.81; H, 4.47; N, 11.2. Calcd: for C₂₃H₂₂ F₆ N₄ O₂ : C, 55.20; H, 4.43; N, 11.2%.

EXAMPLE 2

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-3-methyl-1,2,4-oxadiazole

Acetamideoxime (117 mg) and powdered molecular sieves were suspended indry tetrahydrofuran (10 ml) and stirred under nitrogen for 1 hour.Sodium hydride (63 mg of 60% suspension in oil) was added and themixture heated to 50° C. until all hydrogen evolution had ceased. Theester of Description 2 (500 mg) was dissolved in tetrahydrofuran (2 ml)and added to the above mixture. This mixture was heated at reflux for 2h, cooled, filtered through celite and evaporated in vacuo. The residuewas dissolved in ethyl acetate and washed with water and then brine. Theorganic layer was dried (MgSO₄) and evaporated in vacuo. The residue waspurified by medium pressure chromatography (Lobar) using 25% ethylacetate in petrol as eluant. This afforded the product as a crystallinesolid: mp 85°-86° C.; ¹ H NMR (360 MHz, DMSO-d₆) d 1.47-1.54 (2H, m,CH₂), 1.85-1.89 (1H, m, CHH), 2.13-2.17 (1H, m, CHH), 2.31 (3H, s, CH₃),2.34-2.40 (1H, m, CHHN), 2.98-3.01 (1H, m, CHHN), 3.51 (1H, d, J=15.0Hz, NCHH-oxadiazole), 3.60 (2H, s, NCHCHO), 3.81 (1H, d, J=15.0 Hz,NCHH-oxadiazole), 4.06 (1H, d, J=13.0 Hz, OCHH), 4.62 (1H, d, J=13.0 Hz,OCHH), 7.25-7.31 (3H, m, ArH), 7.43-7.45 (2H, m, ArH), 7.70 (2H, s,ArH), 7.93 (1H, s, ArH); MS (EI) m/z 500 ((M+1)⁺, 100%). Found: C,57.94; H, 4.79; N, 8.23. Calcd. for C₂₄ H₂₃ F₆ N₃ O₂ : C, 57.72; H,4.64; N, 8.41%.

EXAMPLE 3

(+)3-Amino-5-[{(2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-oxadiazole

The title compound was prepared from the ester of Description 4 usingthe procedure described in Example 1: mp 138°-139° C.; [a]²³ _(D)=+147.7° (c=1, MeOH). ¹ H NMR (360 MHz, CDCl₃) d 1.47-1.50 (2H, m, CH₂),1.85-1.89 (1H, m, CHH), 2.14-2.17 (1H, m, CHH), 2.35-2.41 (1H, m, CHHN),2.99-3.02 (1H, m, CHHN), 3.29 (1H, s, NCHCHO), 3.33 (1H, d, J=15.0 Hz,NCHH--het), 3.65 (1H, d, J=15.0 Hz, NCHH--het), 3.60 (1H, brs, NCHPh),4.05 (1H, d, J=13.0 Hz, OCHH), 4.62 (1H, d, J=13.0 Hz, OCHH), 6.20 (2H,s, NH₂), 7.23-7.31 (3 H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s,ArH), 7.93 (1H, s, ArH); MS (CI⁺) m/z 501 (M+1⁺, 75%). Found: C, 54.81;H, 4.47; N, 11.2. Calcd. for C₂₃ H₂₂ F₆ H₄ O₂ : C, 54.98; H, 4.54; N,11.30%.

EXAMPLE 4

3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]pyridiniumhydrochloride.

The compound of Description 1 (410 mg), 3-picolyl chloride (167 mg) andpotassium carbonate were suspended in dimethylformamide (3 ml) and themixture heated at 60° C. for 12 h. The mixture was cooled, diluted withwater (50 ml) and extracted with ethyl acetate (2×10 ml). The organicphase was washed with brine, dried (MgSO₄) and evaporated. The residuewas purified on silica using a gradient elution of 25-50% ethyl acetatein petrol. The product was dissolved in ethereal hydrogen chloride toform the dihydrochloride salt which was recrystallised from benzene: mp198°-200° C. ¹ H NMR (360 MHz, DMSO-d₆, 353K) d 1.68-1.82 (2H, m, CH₂),2.09-2.18 (2H, m, CH₂), 3.06 (1H, mc, CHHN), 3.37 (1H, mc, CHHN), 3.89(1H, s, NCHCHO), 4.16 (1H, brd, NCHH-pyridine), 4.20 (1H, brd,NCHH-pyridine), 4.26 (1H, d, J=13.0 Hz, CHHO), 4.56 (1H, brs, NCHPh),4.72 (1H, d, J=13.0 Hz, CHHO), 7.37-7.41 (3H, m, ArH), 7.60-7.64 (1H, m,ArH), 7.71-7.72 (2H, m, ArH), 7.86 (1H, s, ArH), 7.89 (2H, s, ArH), 8.08(1H, d, J=8.0 Hz, ArH), 8.64 (1H, s, ArH), 8.68 (1H, d, J=5.0 Hz, ArH);MS (CI⁺) m/z 495 (M⁺ +1, 60%); Found: C, 52.45; H, 4.90; N, 4.52. Calcd.for C₂₆ H₂₄ F₆ N₂ O.2HCl.1.5H₂ O: C, 52.54; H, 4.92; N, 4.71%.

EXAMPLE 5

2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]pyridiniumhydrochloride

The compound of Description 1 was reacted with 2-picolyl chloridefollowing the procedure illustrated in Example 4: mp 175°-180° C. ¹ HNMR (360 MHz, DMSO-d₆) d 1.65-1.83 (2H, m, CH₂), 2.08-2.15 (2H, m, CH₂),3.16-3.20 (1H, m, CHHN), 3.30-3.40 (1H, m, CHHN), 3.70 (1H, s, NCHCHO),4.18 (1H, d, J=14.0 Hz, CHH-pyridine), 4.23 (1H, d, J=14.0 Hz,CHH-pyridine), 4.30 (1H, d, J=13.0 Hz, OCHH), 4.79 (1H, d, J=13.0 Hz,OCHH), 4.78 (1H, s, CHPh), 7.24 (1H, d, J=7.5 Hz, ArH), 7.36-7.4 (3H, m,ArH), 7.47-7.51 (1H, m, ArH), 7.62 (2H, mc, ArH), 7.85 (1H, dt, J=7.5,2.0 Hz, ArH), 7.94 (2H, s, ArH), 7.97 (1H, s, ArH), 8.65 (1H, d, J=7.5Hz, ArH); MS (CI⁺) m/z 495 (M+1)⁺, 100%). Found: C, 53.01; H, 4.79; N,4.69. Calcd. for C₂₆ H₂₄ F₆ N₂ O.2HCl.H₂ O: C, 53.30; H, 4.82; N, 4.78%.

EXAMPLE 6

2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]benzimidazole

The compound of Description 1 was reacted with2-(chloromethyl)benzimidazole following the procedure illustrated inExample 4: mp 152°-153° C. ¹ H NMR (360 MHz, DMSO-d₆) d 1.44-1.59 (2H,m, NCH₂ CH₂ CH₂), 1.85-1.89 (1H, m, CHHCH₂ N), 2.15-2.18 (2H, m,NCHH+CHHCH₂ N), 2.86-2.89 (1H, m, NCHH), 3.15-3.19 (1H, d, J=14.0 Hz,NCHH-imidazole), 3.57 (1H, s, NCHCHO), 3.63 (1H, s, NCHCHO), 3.80-3.84(1H, d, J=14.0 Hz, NCHH-imidazole), 4.10-4.13 (1H, d, J=13.0 Hz,--OCHH), 4.63-4.66 (1H, d, J=13.0 Hz, --OCHH), 7.07-7.15 (2H, m, ArH),7.24-7.34 (3H, m, ArH), 7.43-7.52 (2H, m, ArH), 7.60-7.62 (2H, m, ArH),7.67 (2H, s, ArH), 7.94 (1H, s, ArH), 12.10 (1H, s, NH); MS (CI⁺) m/z534 ((M+1)⁺, 100%).

EXAMPLE 7

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]tetrazole

The compound of Description 5 (1.0 g), triethylamine hydrochloride (467mg) and sodium azide (441 mg) were dissolved in 1-methyl-2-pyrrolidinone(5 ml) and the reaction mixture was heated at reflux under nitrogen for2 h. The mixture was then cooled, and diluted with ice/water (80 ml) andacidified to pH=2 with methanolic hydrogen chloride. This precipitatedthe product as a white solid, which was purified on silica using agradient elution of methanol in dichloromethane (0-5%). The product wasrecrystallised from ether-hexane: mp 114°-115° C. ¹ H NMR (360 MHz,DMSO-d₆) d 1.59-1.65 (2H, m, NCH₂ CH₂ CH₂), 2.02-2.22 (2H, m, NCH₂ CH₂),2.39-2.46 (1H, m, CHHN), 2.98-3.02 (1H, m, CHHN), 3.62 (1H, s, NCHCHO),3.66 (1H, s, NCHCHO), 3.70-3.74 (1H, d, J=15.5 Hz, NCHH-tetrazole),4.05-4.10 (1H, d, J=15.5 Hz, NCHH-tetrazole), 4.08-4.12 (1H, d, J=12.0Hz, OCHH), 4.51-4.54 (1H, d, J=12.0 Hz, OCHH), 5.30 (1H, s, NH),7.30-7.35 (3H, m, ArH), 7.45-7.47 (2H, m, ArH), 7.51 (2H, s, ArH), 7.74(1H, s, ArH); MS (CI⁺) m/z 486 (M⁺ +1, 85%). Found: C, 53.14; H, 4.58;N, 13.96. Calcd. for C₂₂ H₂₁ F₆ N₅ O.0.5H₂ O: C, 53.44; H, 4.48; N,14.16%.

EXAMPLE 8

2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-4-methyl-1,3-thiazole

Anhydrous acetone (2 ml) and methanol (2 ml) and tetrabutylammoniumperbromide (111 mg) were stirred under nitrogen to generate a solutionof bromoacetone in situ. The compound of Description 6 (150 mg) wasadded to this mixture and the resulting solution was stirred for 2 h. Asecond equivalent of bromoacetone was added and the mixture was stirredfor a further 2 h. The volatile solvents were removed in vacuo and theresidue was dispersed between aqueous potassium carbonate and ethylacetate. The organic phase was washed with brine, dried (MgSO₄) andconcentrated in vacuo affording a brown oil. This was purified on silicausing a gradient elution of ethyl acetate in petrol (10-30%) which gavethe product as a clear oil: ¹ H NMR (360 MHz, CDCl₃) 1.51-1.68 (2H, m,CH₂), 1.98-2.22 (2H, m, CH₂), 2.26-2.37 (1H, m, NCHH), 2.38 (3H, s,CH₃), 3.18- 3.26 (1H, m, NCHH), 3.47 (1H, d, J=15.0 Hz, NCHH), 3.54 (H,bs, CHO), 3.58 (H, bs, CHPh), 3.94 (1H, d, J=15.0 Hz, NCHH), 4.01 (1H,d, J=12.5 Hz, OCHH), 4.47 (1H, d, J=12.5 Hz, OCHH), 6.80 (1H, s, SCH),7.24-7.35 (3H, m, Ar--H), 7.52-7.54 (2H, m, Ar--H), 7.58 (2H, s, Ar--H),7.72 (1H, s, Ar--H); MS (CI⁺) m/z 515 (M⁺ +1, 100%). Found: C, 58.59; H,4.88; N, 5.48 Calc for C₂₅ H₂₄ F₆ N₂ OS: C, 58.36; H, 4.70; N, 5.44%.

EXAMPLE 9

(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-1-(2-furoyl)-2-phenylpiperidine

The compound of Description 1 (400 mg) and triethylamine (300 mg) weredissolved in dichloromethane and the mixture was stirred for 10 min at0° C. 2-Furoyl chloride (155 mg) was added to the solution and thereaction mixture was stirred for 15 min. The mixture was then washedwith brine; the organic layer was separated, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by chromatography onsilica using 20% ethyl acetate in petrol, affording a clear oil. ¹ H NMR(360 MHz, DMSO-d₆) d 1.6-1.8 (2H, m, CH₂), 1.9-2.1 (2H, m, CH₂), 2.99(1H, mc, CHHN), 4.02 (1H, q, J=5.0 Hz, CHO), 4.0-4.2 (1H, m, CHHN), 4.78(1H, d, J=13.0 Hz, OCHH), 4.86 (1H, d, J=13.0 Hz, OCHH), 5.95 (1H, s,CHPh), 6.62 (1H, s, furan-H), 6.99 (1H, s, furan-H), 7.25-7.36 (3H, m,ArH), 7.51-7.54 (2H, m, ArH), 7.83 (1H, s, furan-H), 7.90 (2H, s, ArH),7.99 (1H, s, ArH); MS (CI⁺) m/z 498 (M⁺ +1, 20%).

EXAMPLE 10

2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]furan

The compound of Example 9 (340 mg) was dissolved in tetrahydrofuran. Tothis solution was added borane-dimethyl sulfide complex (0.18 ml of 10Msolution) and the resulting solution was heated at reflux for 8 h. Themixture was cooled, methanol added to quench excess borane, and thesolvents were removed in vacuo. The residue was dissolved in methanol(10 ml) and potassium carbonate was added (238 mg). This mixture washeated at reflux for 1 hour; the methanol was removed in vacuo and theresidue was dispersed between ethyl acetate and brine. The ethyl acetatelayer was dried (MgSO₄) and evaporated. The residue was purified bychromatography on silica using 10% ethyl acetate in petrol. The productwas recrystallised from ether-hexane: mp 103°-104° C. ¹ H NMR d 1.4-1.5(2H, m, CH₂ CH₂), 1.8-1.9 (1H, m, CHHCH₂ N), 2.1-2.2 (2H, m, CHHCH₂ Nand CHHN), 2.95-3.0 (1H, m, CHHN), 3.11-3.15 (1H, d, J=15.0 Hz,NCHH-furan), 3.38 (1H, s, NCHCHO), 3.54-3.58 (1H, d, J=15.0 Hz,NCHH-furan), 3.56 (1H, s, NCHCHO), 4.02-4.06 (1H, d, J=13.0 Hz, OCHH--), 4.59-4.62 (1H, d, J=13.0 Hz, OCHH--), 6.08-6.09 (1H, m, furan H),6.35-6.36 (1H, m, furan-H), 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H, m,ArH), 7.55 (1H, s, furan-H), 7.68 (2H, s, ArH), 7.93 (1H, s, ArH); MS(CI⁺) m/z 485 (M⁺ +1, 100%). Found: C, 62.11; H, 4.80; N, 2.90. Calcd.for C₂₅ H₂₃ NF₆ O: C, 62.27; H, 4.83; N, 2.96.

EXAMPLE 11

5[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-3-brom-1,2,4-oxadiazolehydrochloride

Diisopropylethylamine (220 μl) was added to a stirred suspension of thecompound of Description 1 (200 mg) and5-bromo-3-(chloromethyl)-1,2,4-oxadiazole (99 mg)(J. Heterocyclic Chem.1989, 26, 23) in dry acetonitrile. The resulting solution was allowed tostir at room temperature for 48 hrs. After this time the solvent wasremoved under reduced pressure and the residual oil purified by columnchromatography on silica using ethyl acetate in hexane (20%) as eluantto afford a waxy solid. Treatment of an ethereal solution of this solidwith ethereal hydrogen chloride yielded a white precipitate.Recrystallisation from ether afforded the title compound as an amorphouswhite solid: mp 100°-102° C. ¹ H NMR (360 MHz, DMSO-d₆) d 1.67-1.70 (2H,m, CH₂), 1.83 (1H, m, CHH), 2.30 (1H, m, CHH), 2.74 (1H, m, CHHN), 3.10(1H, m, CHHN), 3.70 (1H, d, J=11.0 Hz, CH--OCH₂), 3.82 (1H, brs,N--CH--Ph), 4.34 (1H, d, J=16.0 Hz, NCHH-oxadiazole), 4.36 (1H, d,J=11.0 Hz, OCHH--Ar), 4.58 (1H, d, J=16.0 Hz, NCHH-oxadiazole), 4.73(1H, d, J=11.0 Hz, OCHH--Ar), 7.34-7.42 (5H, m, ArH), 7.68 (2H, s, ArH),7.73 (1H, s, ArH); MS (CI⁺) m/z 564 ((M+1)⁺, 20%). Found: C, 45.64; H,3.63; N, 6.70. Calcd. for C₂₃ H₂₀ N₃ O₂ F₆ Br.HCl: C, 45.98; H; 3.52; N,6.99%.

EXAMPLE 12

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-3-dimethylamino-1,2,4-oxadiazolehydrochloride

The compound of Example 11 (169 mg) in dimethylamine (33% in ethanol)was heated to 40° C. for 30 min. The solvent was removed under reducedpressure and the residue purified by column chromatography on silicausing ethyl acetate in hexane (20%) as eluant. The compound wasdissolved in ether and treated with excess ethereal hydrogen chloride toafford a white precipitate. Recrystallisation from ether afforded theproduct as white powder (110 mg): mp 179°-180° C. ¹ H NMR (360 MHz,DMSO-d₆) d 1.59 (2H, m, CH₂), 2.1-2.21 (2H, m, CH₂), 2.4-2.45 (1H, m,CHHN), 3.01 (6H, s, N(CH₃)₂), 3.10 (1H, m, CHHN), 3.60 (1H, brs,CH--O--CH₂), 3.70 (1H, d, J=16.0 Hz, NCHH-oxadiazole), 3.78 (1H, d,J=1.0 Hz, N--CH--Ph), 3.82 (1H, d, J=16.0 Hz, NCHH-oxadiazole), 4.01(1H, d, J=15.0 Hz, O--CHH--Ar), 4.49 (1H, d, J=15.0 Hz, O--CHH--Ar), 7.3(3H, m, ArH), 7.4 (2H, m, ArH), 7.49 (2H, s, ArH), 7.64 (1H, s, ArH); MS(CI⁺) m/z (M⁺ +1) 529. Found: C, 51.87; H, 4.93; N, 9.62. Calcd. for C₂₅H₂₆ N₄ O₂ F₆.HCl.H₂ O. C, 51.51; H, 5.01; N, 9.61%.

EXAMPLE 13

(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(2-thienoyl)piperidine

The compound of Description 1 was reacted with 2-thiophenecarbonylchloride as outlined in Example 9. The oil obtained after work-up andremoval of solvent was purified by chromatography on silica, elutingwith 10% ethyl acetate in petroleum ether to afford the pure product asa clear oil. ¹ H NMR (250 MHz, CDCl₃) d 1.6-1.8 (2H, m, CH₂), 2.1-2.2(2H, m, CH₂), 3.0 (1H, m, CHN), 4.0 (1H, dt, J=5 Hz, 2 Hz, CH), 4.1 (1H,brs, CHN), 4.7 (1H, d, J=7 Hz, CHAr), 4.8 (1H, d, J=7 Hz, CHAr), 6.2(1H, brs, NCHPh), 7.02 (1H, dd, J=1, 2 Hz, thiophene-H), 7.3-7.44 (4H,m, Ar--H), 7.5 (1H, dd, J=1, 3 Hz, thiophene-H), 7.6-7.92 (5H, m,Ar--H).

EXAMPLE 14

(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(2-thienylmethyl)piperidine

The compound of Example 13 was reacted with borane dimethylsulfide asdescribed in Example 10. The free base was recrystallised from ether andhexane to give the product as a white crystalline solid. ¹ H NMR (250MHz, CDCl₃) d 1.44-1.64 (2H, m, CH₂), 1.9-2.2 (2H, m, CH₂), 2.24 (1H, d,J=7 Hz, CHN), 3.14 (1H, d, J=7 Hz, CHN), 3.4 (1H, s, CHO), 3.56 (1H, s,NCHPh), 3.6 (1H, s, CH-thiophene), 4.88 (1H, d, J=10 Hz, CH-thiophene),4.0 (1H, d, J=10 Hz, CHAr), 4.24 (1H, d, J=10 Hz, CHAr), 6.7 (1H, d, J=1Hz, thiophene-H), 6.9 (H, dd, J=2 Hz, 3 Hz, thiophene-H), 7.2 (1H, d,J=3 Hz, thiophene-H), 7.28 (4H, m, Ar--H), 7.5 (3 H, m, Ar--H), 7.68(1H, s, Ar--H). MS m/z 500 (M⁺, 100%).

EXAMPLE 15

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-4-methyl-3-thioxo-1,2,4-triazolehydrochloride

A suspension of the compound of Description 7 (0.50 g) and methylisothiocyanate (0.09 ml) in 1-butanol (10 ml) was heated under refluxfor 10 min. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 ml) was added andthe reaction mixture was heated under reflux for 2.5 h. The solvent wasremoved in vacuo and the residue was partitioned between water and ethylacetate. The organic layer was dried (MgSO₄) and evaporated. The residuewas purified on silica using 5% methanol in dichloromethane as eluant togive the title compound. The product (470 mg) was characterised as thehydrochloride salt. ¹ H NMR (360 MHz, DMSO-d₆) d 1.77-1.93 (2H, m, CH₂),2.05-2.22 (1H, m, CHH), 2.31 (1H, d, J=13.5 Hz, CHH), 3.42 (3H, s, CH₃),3.45-3.51 (1H, m, NCHHCH₂), 3.83 (1H, d, J=12.0 Hz, NCHHCH₂), 3.97 (1H,brs, CHO), 4.24 (1H, d, J=15.5 Hz, N--CHH--het), 4.32 (1H, d, J=15.5 Hz,N--CHH--het), 4.33 (1H, d, J=12.5 Hz, O--CHH), 4.76 (1H, s, NCH), 4.80(1H, d, J=12.5 Hz, O--CHH), 7.42-7.50 (3H, m, ArH), 7.59 (2H, brs, ArH),7.85 (2H, s, ArH), 7.89 (1H, s, ArH), 9.15 (1H, brs, NH); MS (FAB) m/z530 ((M+1)⁺, 13%).

EXAMPLE 16

3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazole

The compound of Description 1 (1.0 g), anhydrous potassium carbonate(0.94 g) and N-formyl-2-chloroacetamidohydrazone (0.46 g), (preparedaccording to Yanagisawa, I., J. Med. Chem. 1984, 27, 849) were heated to60° C. in anhydrous dimethylformamide for 3 h, followed by heating at130° C. for 12 h. The reaction mixture was cooled, diluted with ethylacetate (100 ml) and washed with water, (3×20 ml). The ethyl acetatelayer was dried (MgSO₄), filtered and evaporated to give a brown oil.This was purified on silica using ethyl acetate in petrol (70:30) aseluant. This afforded the product as a white solid. ¹ H NMR (250 MHz,CDCl₃) d 1.6 (2H, m, CH₂), 1.95-2.24 (2H, m, CH₂), 2.34 (1H, m, NCHH),3.06 (1H, m, NCHH), 3.44 (1H, d, NCHH-triazole), 3.5 (1H, bs, CH O), 3.6(1H, bs, NCHPh), 3.8 (1H, d, N--CHH-triazole), 4.04 (1H, d, OCHH--Ar),4.50 (1H, d, OCHHAr), 7.3 (3H, m, ArH), 7.44 (2H, m, ArH), 7.5 (2H, s,ArH), 7.7 (1H, s, ArH), 7.9 (1H, s, triazole-H). MS (CI⁺) m/z 485 (M⁺+1, 35%).

EXAMPLE 17

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole

The compound of Description 7, potassium thiocyanate (0.45 g) and conc.hydrochloric acid (2.3 ml) in water (12 ml) were heated under reflux for2 h. After cooling, solid sodium hydroxide was added until pH=8 and theaqueous layer was extracted with ethyl acetate. The organic layer wasdried (MgSO 4), filtered and evaporated to give the crude semi-carbazidewhich was heated at reflux in 2N sodium hydroxide solution (10 ml) for 2h. After cooling the solution was acidified to pH 5-6 and the productextracted into ethyl acetate. The organic layer was dried (MgSO₄),filtered and evaporated. The crude triazole was chromatographed onsilica eluting with 40% ethyl acetate/60-80 petroleum ether to give thetitle compound as a white solid. ¹ H NMR (250 MHz, CDCl₃) d 1.6 (2H, m,CH₂), 1.9-2.3 (3H, m, CH₂ +NCHH), 2.95 (1H, bd, NCHH), 3.16 (1H, d,N--CHH--Het), 3.20 (1H, bs, CHO), 3.6 (1H, bs, NCHPh), 3.78 (1H, d,N--CHH--Het), 4.1 (1H, d, CHH--Ar), 4.58 (1H, d, CHH--Ar), 7.32 (5H, m,ArH), 7.5 (2H, s, Ar--H), 7.78 (1H, s, ArH). MS (FAB) m/z 517 (M⁺ +1,80%).

EXAMPLE 18

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2-methyltetrazole

The compound of Example 7 (500 mg) was suspended in water (4 ml) andsodium hydroxide (44 mg) added. This was heated to an externaltemperature of 96° C. and dimethyl sulphate (65 mg) added. The reactionmixture was allowed to stir under nitrogen at 96° C. for 1 h after whichtime stirring was continued for 24 h at 5° C. After this time, theproduct was extracted into dichloromethane and washed with water andbrine. The organic layer was dried (MgSO₄) and evaporated. The residuewas purified on silica using medium pressure chromatography (Lobar), andeluted with 25% ethyl acetate in petrol. The first compound to be elutedwas isolated, and this afforded the product (50 mg) as a crystallinesolid, which was recrystallised from ether/hexane to afford whitecrystals: mp 139°-141° C. ¹ H NMR (360 MHz, DMSO) d 1.44-1.51 (2H, m,CH₂), 1.79-1.82 (1H, m, CHH), 2.12-2.15 (1H, m, CHH), 2.19-2.25 (1H, m,CHHN), 2.97-3.00 (1H, m, CHHN), 3.37 (1H, d, J=14 Hz, N--CHH-tetrazole),3.52 (1H, s, NCHCHO), 3.58 (1H, s, NCHCHO), 3.81 (1H, d, J=14 Hz,N--CHH-tetrazole), 4.03 (1H, d, J=13 Hz, OCHH), 4.31 (3H, s, CH₃), 4.60(1H, d, J=13 Hz, OCHH), 7.23-7.33 (3H, m, ArH), 7.49-7.51 (2H, m, ArH),7.68 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI⁺) m/z 500 ((M+1)⁺, 100%).Found: C, 55.56; H, 4.76; N, 14.20. Calculated for C₂₃ H₂₃ N₅ OF₆ : C,55.31; H, 4.64; N, 14.02%.

EXAMPLE 19

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1-methyltetrazole

The title compound was prepared as described in Example 18. Duringpurification, the second compound to be eluted was isolated, and thisafforded the product (120 mg) as a crystalline solid, which wasrecrystallised from ether/hexane to afford yellow crystals: mp 75°-77°C. ¹ H NMR (360 MHz, DMSO) d 1.51-1.55 (2H, m, CH₂), 1.84-1.87 (1H, m,CHH), 2.12-2.16 (1H, m, CHH), 2.31-2.37 (1H, m, CHHN), 2.81-2.84 (1H, m,CHHN), 3.52 (1H, d, J=15 Hz, NCHH-tet), 3.54 (1H, s, NCHCHO), 3.60 (1H,s, NCHCHO), 3.82 (1H, d, J=14 Hz, NCHH-tet), 3.84 (3H, s, CH₃), 4.14(1H, d, J=13 Hz, OCHH), 4.85 (1H, d, J=13 Hz, OCHH), 7.26-7.32 (3H, m,ArH), 7.45-7.48 (2H, m, ArH), 7.74 (2H, s, ArH), 7.94 (1H, s, ArH); MS(CI⁺) m/z 500 ((M+1)⁺, 20%).

EXAMPLE 20

3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-dimethylamino-1,2,4-thiadiazole

a) 5-Dimethylamino-3-(chloromethyl)-1,2,4-thiadiazole

A solution of dimethylamine in ethanol (0.5 ml×33%) was added to astirred suspension of 5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (540mg)(J. Goerdeler, Chem. Ber. 1957, 90, p 182 or ICI EP 0006679) andpotassium carbonate (1.0 g) in methanol. The solution was stirred atroom temperature for three hours, and then the solvent removed underreduced pressure. The residue was taken up in ethyl acetate (40 ml),washed with water (20 ml) and brine (20 ml). The organic layers weredried (MgSO₄), filtered and the solvent removed to afford a yellow gum.Flash chromatography using 10% ethyl acetate in hexane as eluent,afforded the product as a yellow oil (330 mg). ¹ H NMR (360 MHz, CDCl₃)d 3.15 (6H, s, N(CH₃)₂), 4.51 (2H, s, Cl--CH₂); MS (CI⁺) m/z 178((M+1)⁺, 95%).

b) A solution of the compound of Description 1 (223 mg),5-dimethylamino-3-(chloromethyl)-1,2,4-thiadiazole (100 mg) anddiisopropylethylamine (0.2 ml) were heated at reflux in dry acetonitrilefor three hours. The reaction was then allowed to cool to roomtemperature and the solvent removed under reduced pressure. Purificationof the residue by flash chromatography (40% EtOAc/nHex) gave a yellowgum. Recrystallisation from n-hexane afforded the product as yellowplates: mp 144°-145° C. ¹ H NMR (360 MHz, CDCl₃) d 1.57 (2H, m, CH₂),2.11 (3H, m, CH₂ +CHH), 2.42 (1H, m, CHH), 3.11 (6H, s, N(CH₃)₂), 3.20(1H, m, CH--OCH₂), 3.47 (1H, d, J=14.5 Hz, CHH-thiadiazole), 3.56 (1H,m, CHPh), 3.75 (1H, d, J=14.5 Hz, CHH-thiadiazole), 4.03 (1H, d, J=10.5Hz, OCHH--Ar), 4.45 (1H, d, J=10.5 Hz, OCHH--Ac), 7.30 (3H, m, ArH),7.51 (2H, s, ArH), 7.53 (2H, m, ArH), 7.69 (1H, s, ArH); MS (CI⁺) m/z545 ((M+1)⁺, 60%). Found: C, 55.12; H, 4.75; N, 10.38. Calcd. for C₂₅H₂₀ F₆ N₄ SO: C, 55.14; H, 4.81; N, 10.30%.

EXAMPLE 21

2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-4,7-dimethylbenzoxazole

A solution of 2-(chloromethyl)-4,7-dimethylbenzoxazole (285 mg) in dryacetonitrile (10 ml) was added to a solution of the compound ofDescription 1 in dry acetonitrile (10 ml) containingdiisopropylethylamine (0.4 ml). The resulting mixture was heated atreflux for three hours, cooled to room temperature and the residuepurified by flash chromatography on silica gel using 20% ethylacetate/n-hexane as eluant. Recrystallisation of the isolated materialfrom n-hexane afforded the product as white needles: mp 109°-110° C. ¹ HNMR (CDCl₃) 1.49-1.53 (2H, m, CH₂), 1.56-1.60 (1H, m, CHH), 2.03-2.09(1H, m, CHH), 2.10-2.16 (1H, m, CHHN), 2.36-2.40 (1H, m, CHHN), 2.47(3H, s, Ar--CH₃), 2.54 (3H, s, ArCH₃), 3.24 (1H, m, CHN), 3.59 (1H, m,CHOCH₂), 3.67 (1H, d, J=12.0 Hz, N--CHH-benzoxazole), 3.79 (1H, d,J=12.0 Hz, N--CHH-benzoxazole), 3.96 (1H, d, J=10.0 Hz, OCHH), 4.47 (1H,d, J=10.0 Hz, OCHH), 6.99 (2H, s, ArH), 7.32 (3H, m, ArH), 7.54 (2H, s,ArH), 7.57 (2H, m, ArH), 7.71 (1H, s, ArH); MS (CI⁺) m/z 563 ((M+1)⁺,70%). Found: C, 64.09; H, 5.04; N, 5.12. Calcd for C₃₀ H₂₈ N₂ O₂ F₆ : C,64.05; H, 5.01; N, 5.00%.

EXAMPLE 22

2-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]benzoxazole

This compound was prepared following the procedure described in Example21, using 2-(chloromethyl)benzoxazole as the alkylating agent: mp95°-97° C. ¹ H NMR (CDCl₃) d 1.47-1.60 (2H, m, CH₂), 2.06-2.19 (2H, m,CH₂), 2.42-2.56 (1H, dd, 1H, J=6.0, 4.0 Hz, NCHH), 3.26 (1H, dd, J=4.0,2.0 Hz, NCHH), 3.61 (1H, s, CHO), 3.66 (1H, d, J=15.0 Hz,NCHH-benzoxazole), 3.66 (1H, d, J=2.0 Hz, CHPh), 4.02 (1H, d, J=15.0 Hz,CHH-benzoxazole), 4.04 (1H, d, J=12.0 Hz, OCHH), 4.48 (1H, d, J=12.0 Hz,OCHH), 7.26-7.67 (12H, m, ArH); MS (CI⁺) m/z 535 ((M+1)⁺ 65%). Found: C,62.36; H, 4.67; N, 5.27. Calc for C₂₈ H₂₄ F₆ N₂ O₂. 1/4H₂ O: C, 62.39;H, 4.58; N, 5.20%.

EXAMPLE 23

4-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]oxazole

1,3-oxazole-4-carboxaldehyde was prepared following the proceduredescribed by J. Hodges, W. Patt and C. Connolly, J. Org. Chem. 1991, 56,449-452.

a) 4-(Hydroxymethyl)-1,3-oxazole

1,3-Oxazole-4-carboxaldehyde (0.38 g) was dissolved in anhydrousmethanol and stirred under nitrogen; sodium borohydride (0.074 g) wasadded carefully. After 1 hour no starting material was present by TLCusing 50% ethyl acetate in hexane as eluent. The methanol was removed byrotary evaporator (water bath temp 40° C.). The residue was purified bychromatography on silica eluting with 100% diethyl ether. This affordedthe alcohol (0.27 g) as a white solid. ¹ H NMR d (360 MHz, CDCl₃) 2.93(OH), 4.63 (2H, s, CH₂ OH), 7.64 (1H, s, oxazole-H), 7.90 (1H, s,oxazole-H).

b)4-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]oxazole

4-(Hydroxymethyl)-1,3-oxazole (0.13 g) was dissolved in anhydrousdichloromethane (4 ml) under an atmosphere of nitrogen. Triethylamine(0.19 ml) and p-toluenesulfonyl chloride (0.13 g) were added to thereaction mixture which was stirred for 1 hour at room temperature. Afurther portion of p-toluenesulfonyl chloride (0.13 g) and a catalyticamount of dimethylaminopyridine were added to the reaction mixture. Thecompound of Description 3 (1.2 g, free base) was dissolved indimethylformamide (5 ml) and was added to the reaction mixture followedby triethylamine (0.19 ml). The mixture was heated at 60° C. for 2 h andthe resulting mixture was diluted with water (50 ml) and extracted withdichloromethane (3×20 ml). The combined organic layers were dried(MgSO₄) and concentrated in vacuo to afford a yellow oil. This waspurified by chromatography on silica gel using a gradient elution of30-60% ether in hexane to afford the title compound as a white solid.This was recrystallised from ether/hexane: mp 102°-104° C. ¹ H NMR (360MHz, CDCl₃) d 1.46-1.64 (1H, m, NCH₂ CH₂ CHH), 1.7-1.87 (1H, m, NCH₂ CH₂CHH), 1.96-2.20 (2H, m, NCH₂ CH₂), 2.32-2.48 (1H, m, NCHH), 3.20-3.46(3H, m, NCHH+NCHH-oxazole+CHOCH₂ Ar), 3.55 (1H, brs, CHPh), 3.68 (1H, d,J=14.5 Hz, NCHH-oxazole), 4.01 (1H, d, J=11.5 Hz, OCHHAr), 4.46 (1H, d,J=11.5 Hz, OCHHAr), 7.24-7.58 (8H, m, ArH), 7.70 (1H, s, ArH), 7.80 (1H,s, ArH); MS (CI⁺) 485 (M⁺ +1, 100%)

EXAMPLE 24

2-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]pyrazine

a) 2-(Chloromethyl)pyrazine

2-Methylpyrazine (1 g) was dissolved in carbon tetrachloride (50 ml)under nitrogen. N-Chlorosuccinimide (1.42 g) and benzoyl peroxide (50mg) were added and the mixture was heated at reflux for 24 h. Thereaction mixture was cooled and filtered through celite and the filtratewas concentrated in vacuo. The resulting oil was purified on silicausing 30% ethyl acetate in petrol. ¹ H NMR (360 MHz, CDCl₃) d 4.72 (2H,s, CH₂ Cl), 8.56 (2H, s, ArH), 8.76 (1H, s, ArH).

b)2-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]pyrazine

2-(Chloromethyl)pyrazine (0.17 g), potassium carbonate (0.6 g) and thecompound of Description 3 (0.35 g) were suspended in dimethylformamide(3 ml); the reaction mixture was heated at 60° C. for 12 h. The mixturewas cooled, diluted with water (30 ml) and extracted with ethyl acetate(2×20 ml). The combined organic layers were washed with brine, dried(MgSO₄) and concentrated in vacuo to afford a brown oil. The product waspurified by column chromatography on silica gel using a gradient elutionof 15-35% ethyl acetate in hexane. This afforded the product as a whitesolid, which was recrystallised from pentane to give colourlesscrystals: mp 108°-110° C. ¹ H NMR (360 MHz, DMSO-d₆) d 1.42-1.60 (2H, mNCH₂ CH₂ CH₂), 1.77-1.92 (1H, m, NCH₂ CHH), 2.13-2.25 (2H, m, NCHH+NCH₂CHH), 2.84-2.92 (1H, m, NCHH), 3.12 (1H, d, J=14.0 Hz, NCHH-pyrazine),3.55 (1H, m, CHO), 3.63 (1H, m, CHPh), 3.78 (1H, d, 14.0 Hz,NCHH-pyrazine), 4.11 (1 H, d, J=13.0 Hz, OCHHAr), 4.64 (1H, d, J=13.0Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H,s, ArH), 7.93 (1H, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI⁺) 496 (M⁺ +1,60%). Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for C₂₅ H₂₃ F₆ N₃ O: C,60.60; H, 4.68; N, 8.48%.

EXAMPLE 25

4-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2-methyl-1,3-thiazoliumdihydrochloride

4-(Chloromethyl)-2-methylthiazole hydrochloride (83 mg) was added to asuspension of the compound of Description 3 and potassium carbonate indimethylformamide (5 ml). The resulting mixture was heated at 60° C. for18 h, cooled to room temperature and diluted with water (50 ml). Thissolution was extracted with ethyl acetate (2×25 ml) and the combinedorganic extracts were washed with water (2×20 ml), brine (20 ml), dried(MgSO₄) and filtered. The resulting solution was evaporated underreduced pressure to afford a yellow oil. This was purified by mediumpressure liquid chromatography using 50% ethyl acetate in hexane toafford the product as a white solid. This was treated with etherealhydrogen chloride and recrystallised from methyl-t-butyl ether to affordthe title compound: mp 58°-60° C. ¹ H NMR (360 MHz, DMSO-d₆) d 1.71 (2H,m, CH₂), 2.11 (2H, mc, CH₂), 2.49 (1H, m, CHHN), 2.69 (3H, s, AR--CH₃),3.15 (1H, m, CHHN), 3.54 (1H, m, CHO), 4.12 (2H, m, CH₂ -thiazole), 4.16(1H, d, J=10.0 Hz, OCHHAr), 4.58 (1H, brs, CHPh), 4.76 (1H, d, J=10.0Hz, OCHHAr), 7.40-7.43 (5H, m, ArH), 7.64 (1H, brs, ArH), 7.92 (2 H, s,ArH), 7.97 (1H, s, ArH); MS (CI⁺) m/z 515 (M⁺ +1). Found: C, 48.17; H,4.76; N, 4.52. Calcd. for C₂₅ H₂₄ F₆ N₂ OS.2HCl.2H₂ O: C, 48.16; H,4.85; N, 4.49%.

EXAMPLE 26

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-oxadiazolehydrochloride

3-(Chloromethyl)-1,2,4-oxadiazole (270 mg) was added to a rapidlystirred suspension of the compound of Description 3 and potassiumcarbonate in dimethylformamide (10 ml). The reaction mixture heated at60° C. for 4 h, cooled to room temperature and diluted with water (50ml). The aqueous solution was extracted with ethyl acetate (3×50 ml) andthe organic extracts were combined, washed with water (3×50 ml), brine(50 ml), dried (MgSO₄) and filtered. The resulting solution wasconcentrated under reduced pressure and purified by columnchromatography on silica gel using 20% ethyl acetate in hexane aseluent. The resulting oil was treated with ethereal hydrogen chloride toafford the title compound as a white powder: mp 74°-75° C. ¹ H NMR (360MHz, DMSO-d₆) d 1.62 (2H, m, CH₂), 1.97-2.1 (2H, m, CH₂), 2.50 (1H, m,CHHN), 3.16 (1H, m, CHHN), 3.51 (1H, m, CHO), 3.69-3.72 (3H, m, CH₂-oxadiazole+CHPh), 4.14 (1H, d, J=10.0 Hz, OCHHAr), 4.70 (1H, d, J=10.0Hz, OCHHAr), 7.32 (3H, m, ArH), 7.45 (2H, m, ArH), 7.78 (3H, m, ArH),7.94 (1H, s, ArH).

EXAMPLE 27

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-iodo-1,2,4-thiadiazole

a) 5-Iodo-3-(iodomethyl)-1,2,4-thiadiazole

Sodium iodide (excess) was added to a stirred solution of5-chloro-3-(chloromethyl)-1,2,4-thiadiazole (3.0 g)(J. Goerdeler, Chem.Ber. 1957, 90, 182) in dry butanone (15 ml). The resulting solution washeated at reflux for four hours, cooled to room temperature andfiltered. The filtrate was diluted with water (20 ml) and extracted withethyl acetate (50 ml). The ethyl acetate layer was dried (MgSO₄),filtered and concentrated in vacuo to afford a red oil, which was usedin the following reaction without further purification.

b)3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-iodo-1,2,4-thiadiazole

Diisopropylethylamine (116 mg) was added to a stirred solution of5-iodo-3-(iodomethyl)-1,2,4,-thiadiazole (160 mg) and the compound ofDescription 3 (200 mg) in dry acetonitrile (10 ml). The resultingsolution was stirred at room temperature for 18 h. The reaction mixturewas filtered and the solvent was removed in vacuo to afford a red oil.This was purified using column chromatography on silica gel using 20%ethyl acetate in hexane as eluent. This afforded the product as apowder: mp 98°-101° C. ¹ H NMR (360 MHz, CDCl₃) d 1.55 (3H, m, NCH₂ CH₂CH₂ +NCH₂ CHH), 2.13 (2H, m, NCH₂ CHH+NCHH), 2.42 (1H, m, CHHN, 3.21(1H, m, CHO), 3.69 (2H, m, CHPh+CHH-thiadiazole), 4.02 (2H, m,CHH-thiadiazole+OCHH), 4.48 (1H, d, J=8.0 Hz, OCHH), 7.32 (5H, m ArH),7.51 (2H, s ArH), 7.70 (1H, s, ArH).

EXAMPLE 28

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-thiadiazolehydrochloride

Sodium borohydride (280 mg) was added to a stirred solution of thecompound of Example 27 (500 mg) and palladium (II) chloride (280 mg) indry methanol (25 ml). The resulting mixture was stirred for 30 min andthen filtered through celite; the filtrate was concentrated in vacuo.The solid residue thus obtained was dissolved in ethyl acetate and thesolution was washed with water (10 ml), the organic extract was dried(MgSO₄), filtered and concentrated in vacuo to afford a yellow oil.Treatment of this oil with ethereal hydrogen chloride afforded the titlecompound as a white powder: mp 89°-90° C. ¹ H NMR (360 MHz, DMSO-d₆) d1.79 (2H, m, CH₂), 1.9-2.20 (3H, m, CHHN+NCH₂ CH₂), 2.6 (1H, m, CHHN),3.8 (1H, bm, CHO), 3.89 (1H, brs, CHPh), 4.2-4.3 (3H, m, CH₂-thiadiazole+OCHH), 4.76 (1H, d, J=9.0 Hz, OCHH), 7.39 (3H, m, ArH),7.55 (2H, m, ArH), 7.89 (2H, s, ArH), 8.32 (1H, s, ArH), 10.32 (1H, s,N--CH--S); MS (CI⁺) m/z 502 (M⁺ +1). Found: C, 49.31; H, 4.09; N, 7.18%.Calcd. for C₂₃ H₂₁ F₆ N₃ OS.HCl.1.25H₂ O: C, 49.48; H, 4.37; N, 7.52%.

EXAMPLE 29

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-methoxy-1,2,4-thiadiazolehydrochloride

Sodium methoxide (34 mg) was added to a stirred solution of the compoundof Example 27 (200 mg) in methanol (5 ml). The solution was heated atreflux for 2 h, cooled to room temperature and the solvent removed underreduced pressure affording a solid residue. The solid was dissolved inethyl acetate (15 ml), and the organic phase was washed with water (20ml), separated, dried (MgSO₄) and the solvent was removed under reducedpressure. The residual solid was treated with ethereal hydrogen chlorideand the resulting solid was recrystallised from ethyl acetate to affordthe product as while needles: mp 74°-75° C. ¹ H NMR (360 MHz, DMSO-d₆) d1.55 (2H, m, CH₂), 1.73 (1H, m, CHH), 2.09 (2H, m CH₂), 2.43 (1H, m,CHH), 3.20 (1H, m, CHO), 3.49 (2H, m, CHPh+CHH-thiadiazole), 3.75 (1H,m, CHH-thiadiazole), 4.02 (1H, d, J=10.0 Hz, OCHH), 4.14 (3H, s, OCH₃),4.45 (1H, d, J=10.0 Hz, OCHH), 7.30 (3H, m ArH), 7.51 (4H, brs, ArH),7.54 (1H, s, ArH); MS (CI⁺) m/z 532 (M⁺ +1). Found: C, 49.89; H, 4.10;N, 7.41. Calcd. for C₂₄ H₂₃ F₆ N₃ O₂ S.HCl.0.5H₂ O: C, 49.96; H, 4.37;N, 7.28%.

EXAMPLE 30

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazoledihydrochloride

The title compound was prepared according to the procedure described inExample 16, using the compound of Description 3 as starting material.The free base was treated with ethereal hydrogen chloride to afford theproduct as a white crystalline solid: mp (free base) 209°-210° C. Found:C, 49.36; H, 4.57; N, 10.05. Calcd. for C₂₃ H₂₂ F₆ N₄ O.2HCl: C, 49.56;H, 4.34; N, 10.05%.

EXAMPLE 31

5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazolehydrochloride

The title compound was prepared according to the procedure described inExample 17, using the compound of Description 8 as a starting material.This afforded the product as a white solid which was treated withethereal hydrogen chloride to yield the crystalline hydrochloride: mp154°-157° C. Found: C, 46.59; H, 4.52, N, 9.26; Cl, 5.84. Calcd. for C₂₃H₂₂ F₆ N₄ O.HCl.2H₂ O: C, 46.90; H, 4.62; N, 9.51; Cl, 6.02%.

EXAMPLE 32

2-[{(2S,3S)-3-(3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1-(p-toluenesulfonyl)imidazoledihydrochloride

(a) N-(p-Toluenesulfonyl)imidazole-2-carboxaldehyde.

Imidazole-2-carboxaldehyde (1.92 g) was suspended in dichloromethane (20ml). p-Toluenesulfonyl chloride (3.8 g) and triethylamine (2.8 ml) wereadded to the mixture which was stirred at room temperature for 12 hours.The resulting slurry was diluted with water and the organic layer waswashed with brine, dried (MgSO₄) and filtered. The dichloromethane layerwas concentrated in vacuo and the residue was purified by columnchromatography on silica using 50% ethyl acetate in hexane as eluent.This afforded the product as a yellow oil which crystallised onstanding. ¹ H NMR (360 MHz, CDCl₃) d 2.44 (3H, s, ArCH₃), 7.31 (1H, d,J=1.5 Hz, imidazole-H), 7.37 (2H, d, J=8.0 Hz, ArH), 7.83 (1H, d, J=1.5Hz, imidazole-H), 8.00 (2H, d, J=8.0 Hz, ArH), 9.78 (1H, s, CHO). MS(CI⁺) m/z 251 (M⁺ +1).

(b) 2-(Hydroxymethyl)-1-(p-toluenesulfonyl)imidazole

The aldehyde of (a) above (3 g) was dissolved in methanol (15 ml) andsodium borohydride (114 mg) was added portionwise. This solution wasstirred for 10 min. Methanol was removed in vacuo and the residue wasdispersed between ethyl acetate and water. The organic layer wasseparated, dried (MgSO₄) and filtered and the solvent was removed invacuo to afford a crystalline solid. ¹ H NMR (250 MHz, CDCl₃) d 2.42(3H, s, ArCH₃), 4.84 (2H, s, CH₂ O), 7.00 (1H, d, J=1.5 Hz,imidazole-H), 7.36 (2H, d, J=8.0 Hz, ArH), 7.40 (1H, d, J=1.5 Hz,imidazole-H), 7.84 (2H, d, J=8.0 Hz, ArH).

(c) ((N-p-Toluenesulfonyl)imidazol-2-yl)methyl methanesulfonate

The alcohol described in (b) above (12.6 mg) was dissolved indichloromethane (2.5 ml) and triethylamine (0.07 ml). This solution wascooled to 0° C. Methanesulfonyl chloride (0.04 ml) was added to thesolution dropwise. After stirring for 10 mins the solution was dilutedwith water and the organic layer was separated, dried (MgSO₄), filteredand the solvent removed in vacuo to yield a white solid which was usedin the following reaction without further purification. ¹ H NMR (250MHz, CDCl₃) d 2.44 (3H, s, ArH), 2.94 (3H, s, SO₂ CH₃), 5.51 (2H, s, CH₂SO₂), 7.08 (1H, d, J=1.5 Hz, imidazole-H), 7.40 (2H, d, J=8.0 Hz, ArH),7.49 (1H, d, J=1.5 Hz, imidazole-H), 7.92 (2H, d, J=8.0 Hz, ArH).

(d) ((N-p-Toluenesulfonyl)imidazol-2-yl)methylmethanesulfonate (1.6 g)was added to a suspension of the compound of Description 3 (2.47 g) andpotassium carbonate (800 mg) in dimethylformamide (10 ml) and theresulting mixture was heated at 100° C. for 2 h. The mixture was cooled,diluted with water (100 ml) and extracted with ethyl acetate (3×20 ml).The organic extracts were combined, washed with brine, dried (MgSO₄) andconcentrated in vacuo. This afforded a colourless oil which was purifiedby column chromatography on silica using 25-30% ethyl acetate in hexane.This afforded the product as a white crystalline solid which wasrecrystallised from dichloromethane/petrol: mp 125°-126° C. ¹ H NMR (360MHz, DMSO-d₆) d 1.4-1.5 (1H, m, NCH₂ CH₂ CHH), 1.5-1.67 (1H, m, NCH₂ CH₂CHH), 1.8-2.0 (1H, m, NCH₂ CHH), 2.06-2.1 (1H, m, NCH₂ CHH ), 2.35 (3H,s, CH₃), 2.4 (1H, mc, NCHH), 2.7-2.86 (1H, m, NCHH), 3.50 (1H, d, J=14.0Hz, CHH-imidazole), 3.56 (1H, brs, CHO), 3.76 (1H, d, J=1.5 Hz, CHPh),4.08 (1H, d, J=14.0 Hz, CHH-imidazole), 4.09 (1H, d, J=12.0 Hz, OCHH),4.48 (1H, d, J=12.0 Hz, OCHH), 6.96 (1H, d, J=1.0 Hz, imidazole-H), 7.12(2H, d, J=8.5 Hz, ArH), 7.2-7.3 (3H, m, ArH), 7.34 (1H, d, J=1.0 Hz,imidazole-H), 7.46-7.58 (2H, m, ArH), 7.60 (2H, s, ArH), 7.71 (1H, ArH),7.79 (2H, d, J=8.5 Hz, ArH); MS (CI⁺) m/z 638 (M⁺ +1). Found: C, 58.48;H, 4.78; N, 6.72; S, 4.81. Calcd. for C₃₁ H₂₉ F₆ N₃ O₃ S: C, 58.39; H,4.58; N, 6.59; S, 5.03%.

EXAMPLE 33

2-[{2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidino}methyl]imidazoledihydrochloride

The compound of Example 32 was dissolved in dichloromethane and etherealhydrogen chloride was added. The resulting solution was stiffed for 30minutes whereupon the title compound crystallised from solution. Thiswas removed by filtration and recrystallised from ethyl acetate/methanolto afford the title compound as a white crystalline compound. ¹ H NMR(360 MHz, D₂ O) d 1.61-1.74 (1H, m, CHH), 1.76-1.88 (1H, m, CHH),2.04-2.21 (2H, m, CH₂), 3.07-3.23 (1H, m, NCHH), 3.41-3.51 (1H, m,NCHH), 3.66 (1H, s, CHO), 4.09 (1H, d, J=13.0 Hz, OCHH), 4.25 (1H, d,J=15.5 Hz, CHH-imidazole), 4.30 (1H, s, CHPh), 4.39 (1H, d, J=15.5 Hz,CHH-imidazole), 4.55 (1H, d, J=13.0 Hz, OCHH), 7.1-7.2 (3H, m, ArH),7.2-7.3 (2H, m, ArH), 7.38 (2H, s, imidazole-H), 7.48 (2H, s, ArH), 7.51(1H, s, ArH); MS (CI⁺) m/z 484 (M⁺ +1, 25%). Found: C, 50.32; H, 4.92;N, 7.23; Cl, 12.58. Calcd. for C₂₄ H₂₃ F₆ N₃ O.2HCl.H₂ O: C, 50.18; H,4.74; N, 7.32; Cl, 12.34%.

EXAMPLE 34

4-[{2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]imidazoledihydrochloride

This was prepared following the procedure described for Example 33 usingthe compound of Description 3 and 4-(hydroxymethyl)imidazole as startingmaterials. This afforded the title compound as a white crystallinecompound: mp 206°-210° C. ¹ H NMR (360 MHz, D₂ O) d 1.73 (1H, m, NCH₂CH₂ CHH), 1.94-2.06 (1H, m, NCH₂ CH₂ CHH), 2.22-2.40 (2H, m, NCH₂ CH₂),3.33 (1H, mc, NCHH), 3.70-3.81 (1H, m, NCHH), 3.97 (1H, brs, CHO), 4.30(1H, d, J=12.5 Hz, OCHH), 4.42(2H, s, NCH₂ -imidazole), 4.50 (1H, s,NCHPh), 4.75 (1H, d, J=12.5 Hz, OCHH), 7.48 (6H, brs, ArH+imidazole-H),7.74 (2H, s, ArH), 7.95 (1H, s, ArH), 8.80 (1H, s, imidazole-H); MS(CI⁺) m/z 484 (M⁺ +1 Found: C, 50.22; H, 4.82; N, 7.18; Cl, 12.49.Calcd. for C₂₄ H₂₃ F₆ N₃ O.2HCl.H₂ O: C, 50.18; H, 4.74; N, 7.32; Cl,12.34%

EXAMPLE 35

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3,-dihydro-(4H)-3-oxo-1,2,4-triazolehydrochloride

(a) N--Carbomethoxy-2-chloroacetamidrazone

Sodium methoxide (0.032 g) was added to a solution of chloroacetonitrile(1.26 ml) in anhydrous methanol (15 ml) at 0° C. The reaction mixturewas stirred at room temperature for 0.5 hour and then neutralised withacetic acid (0.034 ml). Methyl hydrazinocarboxylate (1.79 g) was addedand the reaction mixture stirred at room temperature for 0.5 hour. Thesolution was concentrated in vacuo to give the title compound as anorange solid. MS (CI)⁺ m/z 166.

(b) The compound of Description 1 (0.50 g) was stirred withN-carbomethoxy-2-chloroacetamidrazone (0.19 g) and potassium carbonate(0.47 g) in dimethylformamide (10 ml) at 70° C. for 18 hours. Thereaction mixture was then stirred at 140° C. for 1 hour. After cooling,the material was partitioned between ethyl acetate and water. Theorganic layer was washed with water, dried (MgSO₄), filtered andconcentrated. The residue was purified by chromatography on silica using5% methanol in ethyl acetate as eluent. The product was recrystallisedfrom ethyl acetate/petrol to give the title compound as a whitecrystalline solid. This was characterised as its hydrochloride salt: mp168°-172° C. MS (CI)⁺ m/z 500 ((M+1)⁺, 18%). Found: C, 50.65; H, 4.43;N, 10.22; Cl, 6.71. Calcd. for C₂₃ H₂₄ N₄ O₂.5 F₆ Cl: C, 50.60; H, 4.43;N, 10.26; Cl, 6.49%.

EXAMPLE 36

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-3-(N,N-dimethylamino)-1,2,4-thiadiazole

(a) 5-(N,N-Dimethylamino)-1,3,4-oxathiazolin-2-one

A solution of chlorocarbonylsulfenyl chloride (11.5 g) in acetonitrilewas added to a suspension of N,N-dimethylurea (25.0 g) in acetonitrile(200 ml), over a period of 20 minutes. The reaction mixture was stirredfor 1 hour at 23° C., then filtered. Methanol (20 ml) was added to thefiltrate to decompose excess chlorocarbonylsulfenyl chloride. Thesolvents were removed in vacuo. The residue was purified bychromatography on silica using dichloromethane in hexane (3:1) to affordthe product as a yellow oil. ¹ H NMR (250 MHz, CDCl₃) d 3.04 (6H, s,(CH₃)₂); MS (CI⁺) m/z 164 (M⁺ +NH₄ ⁺)

(b) 5-(Chloromethyl)-3-(N,N-dimethylamino)thiadiazole Chloroacetonitrile(1.3 ml) in dimethylformamide (1 ml) was heated to 150°-155° C. and5-(N,N-dimethylamino)-1,3,4-oxathiazolin-2-one (1.0 g) was added inportions. After 5 minutes the reaction mixture was cooled andconcentrated in vacuo. The residue was purified by chromatography onsilica using hexane/ethyl acetate (9:1) as eluent. This afforded theproduct as a white crystalline solid. ¹ H NMR (250 MHz, CDCl₃) d 3.19(6H, s, (CH₃)₂), 4.82 (2H, s, CH₂); MS (CI⁺) m/z 178

(c)5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylniperidino}methyl]-3-(N,N-dimethylamino)-1,2,4-thiadiazolehydrochldoride

The compound of Description 1 was reacted with5-(chloromethyl)-3-(N,N-dimethylamino)thiadiazole according to theprocedure described in Example 4. This afforded the title compound as awhite solid: mp 160°-161° C.; ¹ H NMR (360 MHz, DMSO-d₆ +TFA) d1.69-1.87 (2H, m, CH₂), 2.01-2.26 (2H, m, CH₂), 3.10 (6H, s, (CH₃)₂),3.22-3.34 (1H, m, CHH), 3.64-3.72 (1H, m, CHH), 3.90 (1H, s, CHO),4.26-4.34 (2H, m, CH₂), 4.61 (1H, d, J=20.0 Hz, OCHH), 4.76-4.82 (2H, m,OCHH+CHPh), 7.36-7.62 (5H, m, ArH), 7.87 (2H, s, ArH), 7.99 (1H, s,ArH).

EXAMPLE 37

5-[{(2S,3S)-3-(3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]tetrazole

This compound was prepared according to the procedure described inExample 7, using the compound of Description 9 as a starting material:mp 179°-181° C. MS (CI⁺) m/z 486 (MH⁺, 35%). Found: C, 54.61; H, 4.53;N, 14.37. Calcd. for C₂₂ H₂₁ F₆ N₅ O: C, 54.43; H, 4.36; N, 14.43%.

EXAMPLE 38

5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-2-methyltetrazole

This compound was prepared according to the procedure described inExample 18 using the compound of Example 37 as a starting material. Thisafforded the title compound as a white crystalline material: mp158°-159° C. MS (CI⁺) m/z 500 (MH⁺, 70%). Found: C, 55.84; H, 4.66, N,14.13. Calcd. for C₂₃ H₂₃ F₆ N₅ O: C, 55.31; H, 4.64; N, 14.02%.

EXAMPLE 39

5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1-methyltetrazole

This compound was prepared according to the procedure described inExample 19 using the compound of Example 37 as a starting material. Thisafforded the title compound as a dear oil. MS (CI⁺) 500 (MH⁺, 40%).Found: C, 55.27; H 4.69; N, 13.67. Calcd. for C₂₃ H₂₃ F₆ N₅ O: C, 55.31;H, 4.64; N, 14.02%.

EXAMPLE 40

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]pyridazine

(a) 3-(Hydroxymethyl)-1,2-pyridazine 1,2-pyridazine-3-carboxaldehyde(0.89 g)(G. Heinisch, E. Luszczak and M. Pailer, Mh. Chem 104, 1372(1973)) was dissolved in water and sodium borohydride (0.081 g) wasadded carefully. After 1 hour no starting material was present by TLCusing 10% methanol in dichloromethane as eluent. The water was removedin vacuo to afford a gum. The gum was extracted with dichloromethane,the combined organics were dried (MgSO₄) and concentrated in vacuo toafford the alcohol as a solid, which was used in the followingexperiment without further purification. ¹ H NMR (360 MHz, CDCl₃) d 5.04(2H, s, CH₂ OH), 7.54 (1H, dd, pyridazine-H), 7.65 (1H, dd,pyridazine-H), 9.17 (1H, dd, pyridazine-H).

(b)3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]pyridazine

3-(Hydroxymethyl)-1,2-pyridazine was dissolved in anhydrousdichloromethane under an atmosphere of nitrogen and cooled in anice/water bath. Triethylamine (0.68 ml) and methanesulfonyl chloride(0.378 ml) were added and the reaction stirred for 1 hour. No startingmaterial was present by TLC using 5% methanol in dichloromethane aseluent. The solvent was removed in vacuo to afford a solid. The compoundof Description 3 (0.48 g of free base) was dissolved indimethylformamide (5 ml) and added to the solid followed by potassiumcarbonate (0.85 g). The mixture was heated at 60° C. for 12 hours thenpoured into water (75 ml), extracted with ethyl acetate (3×40 ml), dried(MgSO₄) and concentrated to afford a brown oil. This was purified bychromatography on silica gel using a gradient elution of 10-30% ethylacetate in petrol. Further purification was carried out by mediumpressure chromatography; elution with 50/50 ethyl acetate/petrolafforded the title compound as a white solid: mp 111°-113° C. ¹ H NMR d(360 MHz, DMSO-d₆) 1.43-1.66 (2H, m, NCH₂ CH₂ CH₂), 1.77-1.91 (1H, m,NCH₂ CHH), 2.13-2.24 (2H, m, NCHHCHH), 2.75-2.87 (1H, NCHH), 3.27-3.35(1H, d, NCHH-pyridazine), 3.57-3.70 (2H, NCHPh +CHO), 3.83-3.93 (1H, d,NCHH-pyridazine), 4.14 (1H, d, J=13 Hz, OCHHAr), 4.66 (1H, d, J=13 Hz,OCHHAr), 7.23-7.35 (3H, m, Ar--H), 7.50-7.56 (2H, m, ArH), 7.66 (2H, s,pyridazine-H), 7.71 (2H, s, ArH), 7.94 (1H, s, ArH), 9.11 (1H, m, 4H) MS(CI⁺) m/z 496 ((M⁺ +1), 30%)

EXAMPLE 41

2-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,3,5-triazine

The compound of Description 3 (2 g), chloroacetamidine hydrochloride(1.17 g) and diisopropylethylamine (3.17 ml) were dissolved inacetonitrile (10 ml) and the resulting mixture was stirred at 60° C.,under nitrogen, for 12 h. The resulting mixture was evaporated and theresidue was dispersed between ethyl acetate and water. The aqueous layerwas extracted with ethyl acetate (2×50 ml) and dichloromethane (2×50ml). The combined organic fractions were washed with brine, dried(MgSO₄) and evaporated. The residue was purified by chromatography onsilica using 5% methanol in dichloromethane and gradient elution to 10%methanol, 1% aqueous ammonia in dichloromethane. This afforded theintermediate amidine as a semi-solid material, which was not furtherpurified.

The intermediate amidine (2 g) and 1,3,5-triazine (0.35 g) weredissolved in acetonitrile (7 ml) and heated at reflux for 12 h. Thesolution was cooled and evaporated and the residue was purified bychromatography on silica using 50% petrol in ethyl acetate as eluent.This afforded the product as a crystalline solid which wasrecrystallised from hexane: mp 117°-119° C. ¹ H NMR (360 MHz, DMSO-d₆)δ1.41-1.60 (2H, m, NCH₂ CH₂ CH), 1.81-1.94 (1H, m, NCH₂ CHH), 2.12-2.21(1H, m, NCH₂ CHH), 2.34- 2.41 (1H, m, NCHH), 2.99-3.06 (1H, m, CHH),3.26-3.30 (1H, J=15.0 Hz, NCHH-triazine), 3.61 (1H, bs, CHO), 3.71 (1H,bs, CHPh), 3.80 (1H, d, J=15.0 Hz, NCHH-triazine), 4.08 (1H, d, J=13.0Hz, OCHHAr), 4.63 (1H, d, J=13.0 Hz, OCHHAr), 7.18-7.29 (3H, m, ArH),7.48-7.52 (2H, m, ArH), 7.68 (2H, s, ArH), 7.13 (1H, s, ArH), 9.20 (2H,s, triazine-H). MS (CI⁺) m/z, 497 (M⁺ +1, 100%).

EXAMPLE 42

5-[{(2S,3S)-3-((3-t-Butyl-5-methylphenyl)methyloxy)-2-(phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole

The compound of Description 10 was reacted according to the proceduredescribed in Example 35 to afford the title compound as a crystallinesolid: mp 185°-187° C. ¹ H NMR (360 MHz, CDCl₃) δ1.22 (10H, m, C(CH₃)₃+NCH₂ CH₂ CHH), 1.38-1.58 (2H, m, NCH₂ CHHCHH), 1.98-2.26 (5H, m, CH₂+NCHHCHH), 2.89 (1H, d, J=15.0 Hz, NCHH-triazole), 2.96-3.04 (1H, m,NCHH), 3.29 (1H, bs, CHO), 3.56 (1H, bs, CHPh), 3.65 (1H, J=15.0 Hz,NCHH-triazole), 4.13 (1H, d, J=12.0 Hz, OCHHAr), 4.28 (1H, d, J=12.0 Hz,OCHHAr), 6.53 (1H, s, ArH). 6.89 (1H, s, ArH), 7.00 (1H, s, ArH),7.26-7.38 (3H, m, ArH), 7.45-7.50 (2H, m, ArH). MS (CI⁺) m/z 435 (M⁺ +1,60%). Found: C, 72.10; H, 7.94; N, 13.05. Calcd for C₂₆ H₃₄ N₄ O₂ : C,71.86; H, 7.89; N, 12.89%.

EXAMPLE 43

2-[{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-(phenylpiperidino}methyl]imidazoledihydrochloride

The compound of Description 11 was reacted according to the proceduredescribed in Examples 32/33, to afford the title compound: mp 129°-131°C. ¹ H NMR (360 MHz, DMSO-d₆) δ1.84-1.98 (2H, m, NCH₂ CH₂ CH₂),2.14-2.24 (1H, m, NCH₂ CHH), 2.44-2.62 (1H, m, NCH₂ CHH), 3.09-3.20 (1H,m, NCHH), 3.69-3.86 (2H, m, NCHH+CHO), 4.25 (1H, d, J=13.0 Hz, OCHHAr),4.53 (1H, d, J=13.0 Hz, OCHHAr), 4.83 (1H, d, J=15.0 Hz,NCHH-imidazole), 4.91 (1H, bs, CHPh), 5.14 (1H, d, J=15 Hz,NCHH-imidazole), 7.16-7.48 (10H, m, ArH), 7.84 (1H, bs, N--H). MS (CI⁺)m/z 415 (M+ 1⁺, 70%). Found: C, 50.71; H, 5.28; N, 8.05. C₂₂ H₂₃ Cl₂ N₃O.2HCl.2H₂ O requires: C, 50.30; H, 5.56; N, 7.99%.

EXAMPLE 44

5-[{(2S,3S)-3-((3-Chloro-5-methylphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole

The compound of Description 12 was reacted according to the proceduredescribed in Example 35 to afford the title compound as a whitecrystalline solid: mp 227°-228° C. ¹ H NMR (360 MHz, DMSO-d₆) δ1.35-1.55(2H, m, NCH₂ CH₂ CH₂), 1.78-1.88 (1H, m, NCH₂ CHH), 2.06-2.13 (2H, m,NCHHCHH), 2.20 (3H, s, CH₃), 2.73 (1H, d, J=14.0 Hz, NCHH-triazole),2.89 (1H, d, J=11.0 Hz, NCHH), 3.32-3.39 (1H, m, CHO), 3.42 (1H, d,J=14.0 Hz, NCHH-triazole), 3.47 (1H, s, CHPh), 3.86 (1H, d, J=12.0 Hz,OCHH), 4.29 (1H, d, J=12.0 Hz, OCHH), 6.65 (1H, s, ArH), 6.79 (1 H, s,ArH), 7.07 (1H, s, ArH), 7.25-7.34 (3H, m, ArH), 7.51-7.53 (2H, m, ArH).MS (CI⁺) m/z 412 (M⁺ +1, 20%). Found: C, 64.30; H, 6.13; N, 13.67. C₂₂H₂₅ ClN₄ O₂ requires: C, 63.99; H, 6.10; N, 13.57%.

EXAMPLE 45

5-[{(2S,3S)-3-((3,5,-Bis(trifluoromethyl)phenyl)methyloxy-2-(diphenylmethyl)pyrrolidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole

The compound of Description 13 was reacted withN-carbomethoxy-2-chloroacetamidrazone according to the proceduredescribed in Example 35 to afford the product as a white crystallinesolid. ¹ H NMR (250 MHz, CDCl₃) δ1.92 (2H, m), 2.62 (1H, m), 2.90 (1H,d, J=15 Hz), 3.14 (2H, m), 3.78 (2H, m), 4.08 (1H, m), 4.28 (2H, m),7.1-7.4 (10H, m, ArH), 7.48 (2H, s, ArH), 7.77 (1H, s, ArH). MS (CI⁺)m/z 577 (M⁺ +1, 100%).

EXAMPLE 46

5-[{(2R,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-2-(diphenylmethyl)pyrrolidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole

The compound of Description 14 was reacted withN-carbomethoxy-2-chloroacetamidrazone according to the proceduredescribed in Example 35 to afford the title compound as a whitecrystalline solid. ¹ H NMR (360 MHz, CDCl₃) δ2.00 (2H, m), 2.69 (1H, m),3.03 (1H, t, J=7.5 Hz), 3.26 (1H, d, J=14.5 Hz), 3.32 (1H, d, J=14.5Hz), 3.68 (2H, s), 3.76 (1H, d, J=3.5 Hz), 4.31 (1H, d, J=12.5 Hz), 4.42(1H, d, J=12.5 Hz), 7.40-7.19 (10H, m, ArH), 7.64 (2H, s, ArH), 7.76(1H, s, ArH). MS (CI⁺) m/z 577 (M⁺ +1, 100%).

EXAMPLE 47

3-[{2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-(diphenylmethyl)pyrrolidino}methyl]-1,2,4-triazole

The compound of Description 15 was reacted withN-formyl-2-chloroacetamidrazone according to the procedure in Example 16to afford the title compound as a crystalline solid: mp 128°-129° C. ¹ HNMR (360 MHz, DMSO-d₆) δ1.65 (1H, brs), 1.76 (1H, brs), 3.10 (2H, m),3.61 (1H, d, J=12.0 Hz), 3.92 (1H, brs), 4.01 (1H, brs), 4.22 (2H, m),7.02 (2H, d, J=1.8 Hz, ArH), 7.10 (1H, m, ArH), 7.14 (3H, m, ArH), 7.22(2H, t, ArH), 7.39 (2H, d, ArH), 7.46 (3H, m, ArH). MS (CI⁺) m/z 493 (M⁺+1, 60%). Found: C, 65.95; H, 5.22; N, 11.33. Calcd for C₂₇ H₂₆ Cl₂ N₄O: C, 65.72; H, 5.31; N, 11.35%.

EXAMPLE 48

5-[{(2S,3S)-3-((3-t-Butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole

The compound of Description 16 was reacted withN-carbomethoxy-2-chloroacetamidrazone, according to the proceduredescribed in Example 35, to afford the title compound as a whitecrystalline solid: mp 181°-182° C. MS (CI⁺) m/z 455 (M⁺ +1, 100%).Found: C, 65.99; H, 6.87; N, 12.31. Calcd for C₂₅ H₃₁ ClN₄ O: C, 66.47;H, 6.91; N, 12.45%.

EXAMPLE 49

5-[{(2S,3S)-3-((3-Bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazolehydrochloride

The title compound was prepared according to the procedure described inExample 35, using the compound of Description 3 as starting material.The hydrochloride salt was recrystallised from ethyl acetate-methanol togive a white crystalline solid: mp 265°-266° C. ¹ H NMR (360 MHz,DMSO-d₆ +TFA) δ1.75-1.95 (2H, m, CH₂), 2.04-2.30 (2H, m, CH₂), 3.20-3.32(1H, m, NCHH), 3.58-3.69 (1H, m, NCHH), 3.90 (1H, d, J=15.0 Hz,NCHH-triazole), 3.93 (1H, s, CHO), 3.94 (1H, d, J=15.0 Hz,NCHH-triazole), 4.30 (1H, d, J=12.0 Hz, OCHH), 4.73 (1H, bs, CHPh), 4.80(1H, d, J=12.0 Hz, OCHH), 7.42 (3H, brs, ArH), 7.56 (2H, brs, ArH), 7.89(2H, s, ArH), 7.95 (1H, s, ArH). MS (CI⁺) m/z 501 (M⁺ +1), 60%). Found:C, 51.41; H, 4.15; N, 10.58; Cl, 6.46. Calcd for C₂₃ H₂₂ F₆ N₄ O.HCl: C,51.45; H, 4.32; N, 10.44; Cl, 6.60%.

EXAMPLE 50

3-8{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1-methyl-1,2,4-triazolehydrochloride

The compound of Example 30 (0.5 g) was dissolved in methanol in a tube.Sodium (0.03 g) and iodomethane (0.075 ml) were added and the containerwas sealed. The resulting solution was heated at 65° C. for 1 h, cooledand evaporated. The residue was suspended between water and ethylacetate. The organic layer was dried (MgSO₄), filtered and the solventremoved in vacuo. The residue was purified by chromatography on silicausing ethyl acetate as eluent. This afforded the product as a colourlessoil, which was converted to the hydrochloride salt by addition ofethereal hydrogen chloride. The salt was recrystallised fromether/petrol. ¹ H NMR (360 MHz, DMSO-d₆) δ1.70-1.84 (2H, m, CH₂),2.12-2.51 (2H, m, CH₂), 3.36 (3H, s, NCH₃), 3.52 (1H, brs, CHHN), 3.73(1H, brs, CHHN), 3.87 (1H, s, CHO), 4.25 (2H, m, CHH-triazole), 4.28(1H, d, OCHHAr), 4.65 (1H, brs, NCHPh), 4.78 (1H, d, OCHHAr), 7.41 (3H,s, ArH), 7.60 (2H, brs, ArH), 7.93 (2H, s, ArH), 7.96 (1H, s, ArH), 8.05(1H, s, CH=NH (triazole)); MS (CI⁺) m/z 499 (M⁺ +1, 85%).

EXAMPLE 51

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-phenyl-1,2,4-oxadiazolehydrochloride

The compound of Description 3 was reacted with3-chloromethyl-5-phenyl-1,2,4-oxadiazole according to the proceduredescribed in Example 26. The product was characterised as itshydrochloride salt: mp 88°-90° C. ¹ H NMR (360 MHz, CDCl₃, free base)δ1.50-1.64 (2H, m, CH₂), 2.06-2.22 (2H, m, CH₂), 2.44-2.56 (1H, m,CHHN), 3.18-3.28 (1H, m, CHHN), 3.60 (1H, s, CHO), 3.66-3.74 (1H, d,J=15.0 Hz, NCHH-oxadiazole), 3.78 (1H, s, CHPh), 3.88-3.98 (1H, d,J=15.0 Hz, NCHH-oxadiazole), 4.02-4.10 (1H, d, J=12.0 Hz, OCHHAr),4.44-4.52 (1H, d, J=12.0 Hz, OCHHAr), 7.28-7.64 (10H, m, ArH), 7.68 (1H,s, ArH), 8.08-8.18 (2H, m, ArH); MS (CI⁺) m/z 562 (M⁺ +1).

EXAMPLE 52

3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-thiomethyl-1,2,4-triazolehydrochloride

Sodium methoxide (0.001 g) was added to a solution of the compound ofExample 17 (0.10 g) in ethanol (5 ml) and the mixture was heated atreflux for 10 min. Methyl iodide (0.012 ml) in ethanol (1 ml) was addedand the mixture was heated at reflux for 3 h. The solvent was thenremoved in vacuo and the residue was partitioned between ethyl acetateand water. The organic layer was dried (MgSO₄) and concentrated invacuo. The residue was purified by chromatography on silica using 50%ethyl acetate in petrol as eluent. The compound was isolated as thehydrochloride salt by treatment of the free base with methanolichydrogen chloride: mp 105°-107° C. ¹ H NMR (360 MHz, DMSO-d₆ +TFA)δ1.73-1.91 (2H, m, CH₂), 2.05-2.20 (1H, m, CHH), 2.21-2.30 (1H, m, CHH),2.63 (3H, s, CH₃), 3.28 (1 H, m, NCHHCH₂), 3.73 (1H, m, NCHHCH₂), 3.92(1H, brs, CHO), 4.10 (2H, dd, J=20 Hz, 14.5 Hz, NCH₂), 4.29 (1H, d, J=13Hz, OCHH), 4.68 (1H, s, CHPh), 4.79 (1H, d, J=13 Hz, OCHH), 7.42-7.48(3H, m, ArH), 7.57 (2H, brs, ArH), 7.88 (2H, s, ArH), 7.95 (1H, s, ArH).MS (CI⁺) m/z 531 (M⁺ +1, 44%). Found: C, 51.29; H, 4.62; N, 9.79; Cl,6.06. Calcd for C₂₉ H₂₄ F₆ N₄ OS.HCl: C, 50.84; H, 4.44; N, 9.88; Cl,6.25%.

EXAMPLE 53

5-[{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-3-oxo-1,2,4-triazole

The compound of Description 11 was reacted according to the proceduredescribed in Example 35 to afford the title compound which wasrecrystallised from hot dimethylformamide: mp>220° C. ¹ H NMR (360 MHz,DMSO-d₆, 353K) δ1.45-1.58 (2H, m, CH₂), 1.81-1.95 (1H, m, CHH),2.02-2.12 (1H, m, CHH), 2.18 (1H, dt, J=2.5, 11.5 Hz, NCHHCH₂), 2.82(1H, d, J=14.2 Hz, NCHH), 2.94 (1H, brd, NCHHCH₂), 3.40 (1H, d, J=14.5Hz, NCHH), 3.45 (1H, d, CHO), 3.52 (1H, d, CHPh), 3.91 (1H, d, J=12.5Hz, OCHH), 4.34 (1H, d, J=12.5 Hz, OCHH), 7.21-7.37 (5H, m, ArH),7.47-7.55 (3H, m, ArH).

EXAMPLE 54

4-[{(2R*,3R*)-3-((3-Carbomethoxyphenyl)methyloxy)-2-phenylpiperidino}methyl]pyridiniumdichloride

The compound of Description 17 was reacted with 4-picolyl chlorideaccording to the procedure described in Example 4 to afford the titlecompound. ¹ H NMR (250 MHz, CDCl₃) δ1.42-1.61 (2H, m, NCH₂ CH₂ CH₂),1.98-2.18 (3H, m, NCHHCH₂), 2.87-3.04 (2H, m, NCHH-pyridine+NCHH),3.31-3.39 (1H, m, CHO), 3.48-3.54 (1H, m, NCHPh), 3.86 (1H, d, J=14 Hz,NCHH-pyridine), 3.93 (3H, s, OCH₃), 4.06 (1H, d, J=11Hz, OCHHAr), 4.30(1H, d, J=11Hz, OCHHAr), 7.12 (1H, m, ArH), 7.22-7.39 (6H, m, ArH),7.45-7.56 (2H, dd, pyridine-H), 7.77 (1H, bs, ArH), 7.85-7.92 (1H, ArH),8.46-8.55 (2H, dd, pyridine-H). MS (CI⁺) m/z 417 (M⁺ +1, 50%). Found: C,64.10; H, 6.06; N, 5.62. C₂₆ H₂₈ N₂ O₃.2HCl requires: C, 63.80; H, 6.18;N, 5.72%.

EXAMPLE 55

4[{(2R*,3R*)-3-((3-Carboxamidophenyl)methyloxy)-2-phenylpiperidino}methyl]pyridine

The compound of Description 18 was reacted with 4-picolyl chlorideaccording to the procedure described in Example 4 to afford the titlecompound. ¹ H NMR (360 MHz, CDCl₃) 1.43-1.56 (2H, m, NCH₂ CH₂ CH₂),2.00-2.17 (3H, m, NCHHCH₂), 2.88-3.04 (2H, m, NCHH+NCHHAr), 3.35 (1H, m,CHO), 3.54 (1H, bs, CHPh), 3.83 (1H, d, J=14.5 Hz, NCHHAr), 4.08 (1H, d,J=12 Hz, OCHHAr), 4.35 (1H, d, J=12 Hz, OCHHAr), 5.6-6.16 (2H, bs,CONH₂), 7.11-7.74 (11H, m, ArH), 8.48 (2H, d, J=4 Hz, pyridine-H). MS(CI⁺) m/z 402 (M⁺ +1, 20%).

EXAMPLE 56

5-[{(2R*,3R*)-3-((2-Methoxy-3-nitrophenyl)methyloxy)-2-phenylpiperidino}methyl]-3-methyl-1,2,4-oxadiazole

The compound of Description 19 was reacted according to the proceduredescribed in Example 2 to afford the title compound. ¹ H NMR (360 MHz,CDCl₃) δ1.48-1.64 (2H, m, NCH₂ CH₂ CH₂), 2.09-2.25 (2H, m, NCH₂ CH₂),2.37 (3H, s, CH₃), 2.41-2.51 (1H, m, NCHH), 3.12-3.20 (1H, m, NCHH),3.59 (1H, bs, CHO), 3.64 (1H, bs, CHPh), 3.73 (1H, d, J=16 Hz,NCHH--het), 3.80 (3H, s, OCH₃), 3.91 (1H, d, J=16 Hz, NCHH--het), 3.98(1H, d, J=13 Hz, OCHHAr), 4.48 (1H, d, J=13 Hz, OCHHAr), 6.78 (1H, d,J=9 Hz, H), 7.22- 7.37 (3H, m, ArH), 7.48-7.54 (2H, bd, ArH), 8.09-8.14(1H, dd, J=9 Hz, J=3 Hz, ArH), 8.15-8.18 (1H, d, J=3 Hz, ArH). MS (CI⁺)m/z 439 (M⁺ +1, 100%).

EXAMPLE 57

3-Amino-5-[{(2R*,3R*)-3-((5-amino-2-methoxyphenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-oxadiazole

The compound of Description 20 was reacted according to the proceduredescribed in Example 1 to afford the title compound. ¹ H NMR (360 MHz,CDCl₃) δ1.41-1.60 (2H, m, NCH₃ CH₂ CH₂), 2.13-2.24 (2H, m, NCH₂ CH₂),2.31 (1H, m, NCHH), 3.12-3.21 (1H, m, NCHH), 3.39 (1H, d, J=16 Hz,NCHH--het), 3.47 (1H, m, CHO), 3.56 (1H, m, NCHPh), 3.61 (3H, s, OCH₃),3.82 (1H, d, J=16 Hz, NCHH--Het), 4.13 (1H, d, J=13 Hz, OCHHAr), 4.34(1H, d, J=13 Hz, OCHHAr), 5.17 (2H, bs, NH₂), 6.38 (1H, bs, ArH),6.43-6.48 (1H, m, ArH), 6.54-6.58 (1H, d, J=8.5 Hz, ArH), 7.26-7.58 (3H,m, ArH), 7.48-7.54 (2H, m, ArH).

EXAMPLE 58

6-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]uracil

The compound of Description 3 was reacted with 6-(chloromethyl)uracilfollowing the conditions described in Example 4 to afford the titlecompound. ¹ H NMR (360 MHz, CDCl₃) 1.52-1.71 (2H, m, NCH₂ CH₂ CH₂),1.99-2.25 (3H, m, NCHHCH₂), 2.69 (1H, d, J=16 Hz, NCHH-uracil),2.92-3.01 (1H, m, NCHH), 3.38-3.40 (1H, m, CHO), 3.52-3.62 (2H, m,NCHH-uracil+NCHPh), 4.08 (1H, d, J=12 Hz, OCHHAr), 4.49 (1H, d, J=12 Hz,OCHHAr), 5.41 (1H, s, H_(A)), 7.32-7.40 (5H, m, ArH), 7.50 (2H, s, H),7.56 (1H, s, H), 8.64-9.04 (2H, bs, NH+NH). MS (CI⁺) m/z 528 (M+1⁺,100%). C₂₅ H₂₃ N₃ O₃ F₆ requires C, 56.93; H, 4.40; N, 7.97%. Found C,57.16; H, 4.03; N, 7.88%.

EXAMPLE 59

3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-carboxamido-1,2,4-triazole

The compound of Description 1 was reacted with2-chloro-N-carboxamidoacetamidhydrazone according to the proceduredescribed in Example 35. to afford the title compound as a white solid:mp 195° C. υ_(max) (KBr) 1680 cm⁻¹ ; Found: C, 55.14; H, 4.58; N, 12.82.Calcd for C₂₄ H₂₃ F₆ N₅ O₂ : C, 54.65; H, 4.40; N, 13.27%.

EXAMPLE 60

3-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-5-cyano-1,2,4-triazole

The compound of Example 59 (0.61 g) was dissolved in chloroform (10 ml)and the resulting solution was cooled to 0° C. in an ice bath.Triethylamine (2 ml) was added followed by phosphorus oxychloride (1.2ml), dropwise. The solution was stirred at room temperature for 1 h. Thesolvent was removed in vacuo and the residue was dispersed betweenchloroform and sodium hydrogen carbonate. The organic layer was washedwith brine, dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica using 30% petrolin ethyl acetate as eluent. The product was isolated as thehydrochloride salt using ethereal hydrogen chloride: mp 81° C. MS (CI⁺)m/z 510 (M⁺ +1, 60%).

EXAMPLE 61

3-[(1S)-1-{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazole

(a) (±) N-Formyl-2-chloropropionamidohydrazone

Sodium methoxide (0.162 g) was added to a solution of2-chloropropionitrile (10.5 g) in anhydrous methanol (150 ml) at 0° C.The reaction mixture was stirred at room temperature for 1 h, thenneutralised with acetic acid (0.18 ml). N-Formylhydrazine (7.04 g) wasadded and the mixture was stirred overnight. The resulting pink solutionwas concentrated in vacuo to give the title compound as a pink solid.

(b) The compound of Description 11 (5.9 g) was dissolved indimethylformamide (46 ml ) an d N-formyl-2-chloropropionamidohydrazone(3.5 g) was added, followed by potassium carbonate (5.7 g). The mixturewas stirred at room temperature for 2 h, then diluted with xylene (150ml) and heated at reflux for 2 h. When cool, the mixture was filteredand concentrated in vacuo to afford a brown residue. Crude ¹ H NMRindicated a mixture of diastereoisomers in 3:1 ratio. The residue waspurified by medium pressure chromatography (Lobar) on silica using 4%methanol in dichloromethane as eluent. The first product eluted,diastereoisomer 1, was isolated as a foam which was recrystallised frontether-hexane: mp 105°-107° C. ¹ H NMR (360 MHz, CDCl₃) δ1.31 (3H, d,J=7.0 Hz, --CHCH₃), 1.52-1.59 (2H, m, NCH₂ CHHCHH), 2.02-2.05 (1H, m,NCH₂ CHH), 2.05-2.16 (1H, m, NCH₂ CH₂ CHH), 2.51 (1H, t, J=11.5 Hz,NCHH), 2.62 (1H, m, NCHH), 3.56 (1H, s, CHO), 3.77 (1H, s, CHPh), 3.99(1H, d, J=12.0 Hz, OCHH), 4.22 (1H, q, J=7.0 Hz, --CHCH₃), 4.30 (1H, d,J=12.0 Hz, OCHH), 6.89 (2H, d, J=2.0 Hz, ArH), 7.21 (1H, t, J=2.0 Hz,ArH), 7.3-7.4 (3H, m, ArH), 7.40-7.47 (2H, m, ArH), 7.89 (1H, s,triazole-2H). MS (CI⁺) m/z.

EXAMPLE 62

3-[(1R)-1-(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino}ethyl]-1,2,4-triazole

The second product isolated from the column described in Example 61 wasrecrystallised from ether to afford the title compound whosestereochemistry was established from ¹ H NMR n.O.e. experiments: mp132°-134° C. ¹ H NMR (360 MHz, DMSO-d₆) δ1.06-1.15 (1H, m, NCH₂ CH₂CHH), 1.35 (3H, d, J=7.0 Hz, CHCH₃), 1.34-1.42 (1H, m, NCH₂ CHH),1.66-1.85 (2H, m, NCHHCHH), 1.98-2.02 (1H, m, NCH₂ CH₂ CHH), 3.01-3.03(1H, d, J=10.5 Hz, NCHH), 3.39 (1H, s, CHO), 3.86 (1H, d, J=13.0 Hz,OCHH), 3.98 (1H, q, J=7 Hz, CHCH₃), 4.33 (1H, d, J=13.0 Hz, OCHH), 6.92(1H, d, J=2.0 Hz, ArH), 7.26-7.46 (6H, m, ArH,

EXAMPLE 63

3-[{(2S,3S)-3-((2,3-Dimethylphenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazole

Following the method described in Example 16, the compound ofDescription 23 (100 mg) was reacted with 69 mg ofN-formyl-2-chloroacetamidohydrazone, to give the title compound. ¹ H NMR(CDCl₃) δ1.50 (2H, m), 1.94 (3H, s), 2.0- 2.35 (3H, m), 2.2 (3H, s),3.02 (1H, m), 3.45 (2H, m), 3.57 (1H, s), 3.95 (1H, br s), 3.95 (1H, d,J=11 Hz), 4.26 (1H, d, J=11 Hz), 6.86 (1H, d, J=7 Hz), 7.06 (1H, d, J=7Hz), 7.2-7.5 (6H, m), 7.7 (1H, br s).

The following compounds were prepared by the procedure described inExample 35.

EXAMPLE 64

5-[{(2S,3S)-3-((2,3-Dimethylphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

The compound of Description 23 was used as starting material. ¹ H NMR(CDCl₃) δ1.4-1.55 (2H, m), 1.89 (3H, s), 1.9-2.2 (3H, m), 2.15 (3H, s),2.91 (1H, d, J=15 Hz), 2.95 (1H, m), 3.28 (1H, s), 3.50 (1H, s), 3.66(1H, d, J=15 Hz), 4.06 (1H, d, J=12 Hz), 4.29 (1H, d, J=12 Hz), 6.77(1H, d, J=7 Hz), 6.9 (1H, t, J=7 Hz), 6.97 (1H, d, J=7 Hz), 7.2-7.45(5H, m).

EXAMPLE 65

5-[{(2S,3S)-2-Phenyl-3-((3-(trifluoromethyl)phenyl)methyloxy)piperidino}methyl]-3-oxo-1,2,4-triazole

The compound of Description 21 was used as starting material. ¹ H NMR(CDCl₃) δ1.5 (2H, m), 1.9-2.2 (3H, m), 2.91 (1H, d, J=15 Hz), 3.0 (1H,m), 3.3 (1H, s), 3.5 (1H, s), 3.64 (1H, d, J=15 Hz), 4.12 (1H, d, J=12Hz), 4.41 (1H, d, J=12 Hz), 7.0-7.45 (9H, m), 9.9 (2H, br s).

EXAMPLE 66

5-[{(2S,3S)-3-((3,4-Dichlorophenyl)methyloxy)-2-phenylpiperidino}methyl]-3-oxo-1,2,4-triazole

The compound of Description 22 was used as starting material. ¹ H NMR(CDCl₃) δ1.5 (2H, m), 1.85-2.2 (3H, m), 2.88 (1H, d, J=15 Hz), 3.0 (1H,m), 3.27 (1H, s), 3.48 (1H, s), 3.67 (1H, d, J=15 Hz), 4.05 (1H, d, J=12Hz), 4.35 (1H, d, J=12 Hz), 6.7 (1H, br d, J=7 Hz), 6.95 (1H, br s),7.16 (1H, d, J=7 Hz), 7.2-7.45 (5H, m), 9.8 (1H, br s), 10.5 (1H, br s).

EXAMPLE 67

5-[{(2S,3S)-3-((3-t-Butylphenyl)methyloxy)-2-phenylpiperidino}methyl]-3-oxo-1,2,4-triazole

The compound of Description 24 was used as starting material ¹ H NMR(CDCl₃) δ1.23 (9H, s, C(CH₃)₃), 1.40-1.51 (2H, m, CH₂), 1.82-1.85 (1H,m, CHH), 2.01-2.14 (2H, m, CHH and NCHH), 2.74 (1H, d, J=14 Hz,NCHH-triazolone), 2.88 (1H, m, NCHH), 3.38 (1H, d, J=14 Hz,NCHH-triazolone), 3.40 (1H, m, NCHCHO), 3.51 (1H, s, NCHCHO), 3.85 (1H,d, J=12 Hz, OCHH), 4.23 (1H, d, J=12 Hz, OCHH), 6.80-6.82 (1H, m, ArH),7.06-7.34 (6H, m, ArH), 7.53-7.55 (2H, m, ArH), 11.16 (1H, s, NH), 11.24(1H, s, NH); MS (CI⁺) m/z 420 (M⁺ +1, 10%). Found: C, 71.51; H, 7.51; N,13.08. Cacld. for C₂₅ H32N₄ O: C, 71.40; H, 7.67; N, 13.32%.

EXAMPLE 68

5-[{(2R*,3R*)-3-((3,5-Dimethylphenyl)methyloxy)-2-phenylpiperidino}methyl]-3-oxo-1,2,4-triazole

The compound of Description 25 was used as starting material. ¹ H NMR(360 MHz, DMSO-d₆) δ1.41-1.47 (2H, m, CH₂), 1.81-1.85 (1H, m, CHH),2.05-2.11 (2H, m, CHH and NCHH), 2.15 (6H, s, CH₃), 2.72 (1H, d, J=14Hz, NCHH-triazolone), 2.86-2.89 (1H, m, NCHH), 3.36 (1H, d, J=2.5 Hz,CHO), 3.40 (1H, d, J=14 Hz, NCHH-triazolone), 3.44 (1H, brs, CHPh), 3.82(1H, d, J=12 Hz, OCHH), 4.20 (1H, d, J=12 Hz, OCHH), 6.50 (2H, s, ArH),6.79 (1H, s, ArH), 7.25-7.33 (3H, m, ArH), 7.51-7.53 (2H, m, ArH), 11.16(1H, s, NH), 11.25 (1H, s, NH).

EXAMPLE 69

(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenyl-1-(3-(1,2,4-triazolyl))piperidine

1-Hydroxybenzotriazole hydrate (308 mg),1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (436 mg),triethylamine (0.3 ml) and 1,2,4-triazole-3-carboxylic acid (129 mg)were dissolved in dimethylformamide (5 ml) and the resulting mixture wasstirred for 15 min. The compound of Description 3 (0.5 g) was added andthe resulting mixture was stirred at room temperature for 12 h. Thereaction mixture was diluted with water (100 ml) and the product wasextracted into ethyl acetate (3×50 ml). The organic fractions werewashed successively with citric acid (aqueous), water, potassiumcarbonate and brine, then dried (MgSO₄) filtered and concentrated. Theresidue was purified by column chromatography on silica using 70% ethylacetate in hexane as eluant. The product was recrystallised from ethylacetate/petrol to afford a crystalline white solid: mp 77°-79° C. MS(CI⁻) m/z 478 ((M--HF)⁻, 100%).

EXAMPLE 70

(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-1-(1-oxo-2-pyrid-4-yl)ethyl-2-phenylpiperidiniumhydrochloride

The compound of Description 3 was reacted with 4-pyridylacetic acidfollowing the procedure outlined in Example 69. This afforded acolourless oil which was treated with ethereal hydrogen chloride and thesolid obtained was recrystallised from benzene/hexane. MS (CI⁺) m/z 523(M⁺ +1, 100%). Found: C, 54.67; H, 4.86; N, 4.66; Cl, 6.16. Calcd. forC₂₇ H₂₄ F₆ N₂ O₂.2H₂ O: C, 54.50; H, 4.91; N, 4.70; Cl, 5.96%.

EXAMPLE 71

(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy-1-(2-oxo-2-pyrid-3-yl)ethyl-2-phenylpiperidine

3-(Bromoacetyl)pyridinium hydrobromide (336 mg) was dissolved indimethylformamide (3 ml) and to this solution was added the compound ofDescription 3 (440 mg) followed by potassium carbonate (550 mg). Themixture was stirred at room temperature for 2 h, diluted with water andextracted into ethyl acetate. The organic phase was washed with brine,dried (MgSO₄) and evaporated. The residue was purified by chromatographyon silica using 70% ether in hexane as eluant and further purified bymedium pressure chromatography (Lobar) using ethyl acetate in hexane(60:40) as eluant. ¹ H NMR (250 MHz, DMSO-d₆) δ1.4-1.6 (2H, m), 1.8-1.98(1H, m, CHH), 2.06-2.2 (1H, m, CHH), 2.5-2.6 (1H, m), 2.9-3.0 (1H, m),3.54 (1H, d, NCHHCO), 3.62 (1H, brs, CHO), 3.74 (1H, d, CHPh), 3.84 (1H,d, OCHH), 7.2-7.3 (2H, m, ArH), 7.38-7.5 (3H, m, ArH), 7.5 (1H, dd,pyr-H), 7.85 (2H, s, ArH), 7.92 (1H, s, ArH), 8.14 (1H, dt, pyr-H), 8.62(1H, dd, pyr-H), 8.94 (1H, d, pyr-H).

EXAMPLE 72

3-[(1S)-1-{(2S,3S)-3-((3,5-Bis(trifluoromethylphenyl)methyloxy)-2-phenylpiperidino}ethyl]-1,2,4-triazole

This was prepared from the compound of Description 3 andN-formyl-2-chloropropionamidohydrazone following the procedure describedin Example 61. The first compound to be eluted from the column (using 3%methanol in dichloromethane as eluant on silica) was isolated andcharacterised as the title compound: mp 66°-68° C. MS (CI⁺) m/z 499((M+1)⁺, 100%).

EXAMPLE 73

3-[(1R)-1-{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}ethyl]-1,2,4-triazole

The second product isolated from the column described in Example 72 wasrecrystallised from ethyl acetate/hexane to afford the title compound:mp 108°-111° C. MS (CI⁺) m/z 499 ((M+1)⁺, 100%).

EXAMPLE 74

5-[(1S)-1-{(2S,3S)-3-((3,5-Bis(trifluoromethylphenyl)methyloxy)-2-phenylpiperidino}ethyl]-2,3-dihydro-3-oxo-1,2,4-triazole

This compound was prepared according to the procedure described inExample 35 using the compound of Description 3 andN-carbomethoxy-2-chloropropionamidohydrazone (ClCH(CH₃)C(═NH)NHNHCOOCH₃)as starting materials. ¹ H NMR (CDCl₃) δ0.94 (3H, d, J=7 Hz), 1.4-1.58(2H, m), 1.8 (1H, mc), 2.06-2.2 (1H, m), 2.26-2.4 (1H, m), 3.3 (1H, mc),3.52 (1H, s), 3.64-3.72 (2H, m), 4.06 (1H, d, J=12 Hz), 4.64 (1H, d,J=12 Hz), 7.2-7.38 (3H, m), 7.6-7.7 (2H, m), 7.74 (2H, s), 7.94 (1H, s).MS (CI⁺) m/z 515 ((M+1)⁺, 23%).

EXAMPLE 75

3-[{(2S,3S)-3-((3,5-Dichlorophenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazole

This was prepared from the compound of Description 11 according to theprocedure described in Example 16 to afford the title compound: mp208°-212° C. MS (CI⁺) m/z 417 ((M+1)⁺, 100%).

EXAMPLE 76

5-[{(2R*,3R*)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl)piperdino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

This was prepared from the compound of Description 26 according to theprocedure described in Example 35: mp 125°-127° C. ¹ H NMR (360 MHz,DMSO) δ1.46-1.52 (2H, m), 1.9-1.95 (1H, m), 2.0-2.2 (2H, m) 2.92 (1H, d,J=15 Hz, NCHHtriazolone), 2.98 (1H, mc), 3.35 (1H, s, CHO), 3.44 (1H, d,J=15 Hz, NCHHtriazolone), 3.50 (1H, brs, CHPh), 3.96 (1H, d, J=12 Hz,OCHH), 4.43 (1H, d, J=12 Hz, OCHH), 7.15-7.22 (2H, m, ArH), 7.37-7.41(2H, m, ArH), 7.48 (2H, s, ArH), 7.65 (1H, s, ArH). MS (CI⁺) m/z 535,537 (M⁺ +1, 100, 30%).

EXAMPLE 77

5-[{(2S,3S)-3-((3,4-Dimethylphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

This compound was prepared according to the procedure described inExample 35 using the compound of Description 29 as starting material. ¹H NMR (CDCl₃) δ1.37-1.55 (2H, m), 1.9-2.2 (3H, m), 2.1 (3H, s), 2.15(3H, s), 2.85 (1H, d, J=15 Hz), 2.97 (1H, m), 3.26 (1H, s), 3.51 (1H,s), 3.65 (1H, d, J=15 Hz), 4.06 (1H, d, J=11 Hz), 4.26 (1H, d, J=11Hz),6.65 (2H, m), 6.9 (1H, d, J=8 Hz), 7.2-7.45 (5H, m), 9.5 (1H, brs).

EXAMPLE 78

5-[{(2S,3S)-3-((3-Propoxyphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

This compound was prepared according to the procedure described inExample 35 using the compound of Description 30 as starting material. ¹H NMR (CDCl₃) δ1.25 (6H, d, J=6 Hz), 1.35-1.55 (2H, m), 1.9-2.2 (3H, m),2.89 (1H, d, J=15 Hz), 2.99 (1H, d, J=10 Hz), 3.27 (1H, s), 3.51 (1H,s), 3.66 (1H, d, J=15 Hz), 4.1 (1H, d, J=12 Hz), 4.38 (1H, m), 6.48 (1H,d, J=7 Hz), 6.57 (1H, s), 6.66 (1H, d, J=7 Hz), 7.2-7.5 (5H, m).

EXAMPLE 79

5-[{(2S,3S)-3-((3-Fluoro-5-methylphenyl)methyloxy)-2-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

This was prepared by the reaction of the compound of Description 27according to the procedure outlined in Example 35: mp 228°-229° C. ¹ HNMR (360 MHz; DMSO) δ1.4-1.55 (2H, m, CH₂), 1.8-1.9 (1H, m, CH₂),2.02-2.18 (2H, m, CH₂ and NCHH), 2.21 (3H, s, CH₃), 2.73 (1H, d,NCHH--het, J=14 Hz), 2.87-2.90 (1H, d, NCHH, J=11 Hz), 3.32-3.40 (1H, m,NCHCHO), 3.41 (1H, d, NCHH--het, J=14 Hz), 3.46 (1H, s, NCHCHO), 3.87(1H, d, OCHH--Ar, J=12.5 Hz), 4.28 (1H, d, OCHH--Ar, J=12.5 Hz),6.50-6.55 (2H, m, ArH), 6.80-6.83 (1H, m, ArH), 7.29-7.31 (3H, m, ArH),7.51-7.53 (2H, m, ArH), 11.18 (1H, s, NH), 11.28 (1H, s, NH). MS (CI⁺)m/z 397 (M⁺ +1, 10%).

EXAMPLE 80

5-[{3-(3R*)-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-methyl-2-(2R*)-phenylpiperidino}methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

This was prepared from the compound of Description 28 according to theprocedure outlined in Example 35. ¹ H NMR (360 MHz, MeOD) δ1.43 (3H, s,CH₃), 1.46 (1H, m), 1.91 (3H, m), 2.57 (2H, m), 2.98 (1H, d, J=15 Hz,NCHHtriazolone), 3.21 (2H, m), 3.58 (1H, d, J=15 Hz, NCHH triazolone),3.72 (1H, d, J=12 Hz, OCHH), 4.36 (1H, d, J=12 Hz, OCHH), 7.18 (1H, t,ArH), 7.25 (2H, t, ArH), 7.37 (2H, s, ArH), 7.53 (1H, s, ArH), 7.56 (1H,s, ArH), 7.71 (1H, s, ArH).

EXAMPLE 81

5-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-(3-fluorophenyl)piperidino}methyl]2,3-dihydro-(4H)-3-oxo-1,2,4-triazole

¹ H NMR (CDCl₃) δ1.42-1.62 (2H, m), 1.84-2.2 (3H, m), 2.86-3.1 (2H, m),3.38-3.58 (3H, m), 4.08 (1H, d, J=12 Hz, OCHH), 4.54 (1H, d, J=12 Hz,OCHH), 6.92-7.04 (1H, m, ArH), 7.16-7.32 (3H, m, ArH), 7.54 (2H, s,ArH), 7.76 (1H, s, ArH).

EXAMPLE 82

3-[{(2S,3S)-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino}methyl]-1,2,4-triazine.

(a) The compound of Description 3 (1 g) was dissolved indimethylformamide (8 ml) and N-t-butyloxycarbonyl-2-chloroacetamidrazone(0.6 g) was added, followed by potassium carbonate (0.9 g). The mixturewas stirred at room temperature overnight. The mixture was diluted withwater, extracted with ethyl acetate and the organic layer was washedwith brine, dried (MgSO₄) and evaporated. The residue was purified bycolumn chromatography on silica using ethyl acetate as eluant. Thisafforded the compound as a white solid which was recrystallised fromether-hexane. ¹ H NMR (360 MHz, CDCl₃) δ1.40 (9H, s, (CH₃)₃), 1.42-1.6(3H, m), 2.13-2.2 (2H, m), 2.62 (1H, d, J=15 Hz, NCHHC═NH), 3.07-3.10(1H, m, CHHN), 3.36 (1H, d, J=15 Hz, NCHHC═NH), 3.38 (1H, s, CHO), 3.57(1H, brs, CHPh), 4.02 (1H, d, J=12 Hz, OCHH), 4.45 (1H, d, J=12 Hz,OCHH), 7.25-7.40 (5H, m, ArH), 7.53 (2H, s, ArH), 7.73 (1H, s, ArH).

(b) The Boc-protected amidrazone (1 g) was dissolved in methanolichydrogen chloride and stirred for 12 h. The solvent was evaporated andthe crude product was used in subsequent reactions without furtherpurification.

(c) The amidrazone hydrochloride of (b) above (200 mg) was dissolved inethanol (2 ml). Magnesium sulphate was added (100 mg) and the mixturestirred for 30 min. Triethylamine (0.06 ml) was added followed byglyoxal (90 mg, trimeric dihydrate). This mixture was allowed to stirfor 12 h. The solvent was removed in vacuo and the residue was dispersedbetween ethyl acetate and water. The organic layer was dried (MgSO₄) andconcentrated to afford a brown oil. This was purified by columnchromatography on silica using hexane in ethyl acetate (95%) to affordthe title compound. ¹ H NMR (360 MHz, CDCl₃) δ1.53-1.72 (2H, m, CH₂),1.98-2.22 (2H, m, CH₂), 2.42-2.53 (1H, m, NCHH), 3.14-3.22 (1H, m,NCHH), 3.61 (1H, bs, CHO), 3.74-3.81 (2H, m, NCHPh+OCHH), 4.04 (1H, d,J=12 Hz, NCHHtriazine), 4.19 (1H, d, J=12 Hz, OCHH), 4.47 (1H, d, J=12Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48-7.6 (4H, m, ArH), 7.70(1H, s, ArH), 8.6 (1H, s, ArH). MS (CI⁺) m/z 497 (M⁺ +1, 100%).

The following examples illustrate pharmaceutical compositions accordingto the invention.

EXAMPLE 83

A Tablets containing 1-25 mg of compound

    ______________________________________                                                      Amount mg                                                       ______________________________________                                        Compound of formula (I)                                                                        1.0        2.0    25.0                                       Microcrystalline cellulose                                                                     20.0       20.0   20.0                                       Modified food corn starch                                                                      20.0       20.0   20.0                                       Lactose          58.5       57.5   34.5                                       Magnesium Stearate                                                                             0.5        0.5    0.5                                        ______________________________________                                    

EXAMPLE 83

Tablets containing 26-100 mg of compound

    ______________________________________                                                       Amount mg                                                      ______________________________________                                        Compound of formula (I)                                                                        26.0      50.0    100.0                                      Microcrystalline cellulose                                                                     80.0      80.0    80.0                                       Modified food corn starch                                                                      80.0      80.0    80.0                                       Lactose          213.5     189.5   139.5                                      Magnesium Stearate                                                                             0.5       0.5     0.5                                        ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 84

Parenteral injection

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1 to 100 mg                                            Citric Acid Monohydrate                                                                              0.75 mg                                                Sodium Phosphate       4.5 mg                                                 Sodium Chloride        9 mg                                                   Water for Injections   to 1 ml                                                ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 85

Topical formulation

    ______________________________________                                                             Amount mg                                                ______________________________________                                        Compound of formula (I)                                                                              1-10 g                                                 Emulsifying Wax        10 g                                                   Liquid paraffin        20 g                                                   White Soft Paraffin    to 100 g                                               ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

    __________________________________________________________________________    SEQUENCE LISTING                                                              (1) GENERAL INFORMATION:                                                      (iii) NUMBER OF SEQUENCES: 3                                                  (2) INFORMATION FOR SEQ ID NO:1:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 11 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                       Met LeuGlyPhePheGlnGlnProLysProArg                                            1510                                                                          (2) INFORMATION FOR SEQ ID NO:2:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                    (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                      MetLeuGlyValPheSerAspThrLysHis                                                1510                                                                          (2) INFORMATION FOR SEQ ID NO:3:                                              (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 10 amino acids                                                    (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                          (ii) MOLECULE TYPE: protein                                                   (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                       MetLeuGlyValPhePheAspHisMetAsp                                                1510                                                                      

We claim:
 1. A compound of formula (I), or a salt or prodrug thereof:##STR13## wherein: n is 3;X represents O or S; Y represents ahydrocarbon chain of 1, 2, 3, or 4 carbon atoms which may optionally besubstituted by oxo; R¹ represents unsubstituted phenyl or phenylsubstituted with 1, 2 or 3 substituents selected from the groupconsisting of: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, cyano,nitro, trifluoromethyl, trimethylsilyl, --OR^(a), --SR^(a), --SOR^(a),--SO₂ R^(a), --NR^(a) R^(b), --NR^(a) COR^(b), --NR^(a) CO₂ R^(b), --CO₂R^(a), and --CONR^(a) R^(b) ; R² represents phenyl or benzhydryl,wherein the phenyl or benzhydryl moiety is unsubstituted or substitutedwith a substituent selected from the group consisting of: C₁₋₆ alkyl,C₁₋₆ alkoxy, halo, and trifluoromethyl; R⁴ and R⁵ may be present on anyavailable carbon atom of the azacyclic ring and are each independentlyselected from the group consisting of: hydrogen, halo, C₁₋₆ alkyl, oxo,CH₂ OR^(a), CO₂ R^(a), and CONR^(a) R^(b) ; R⁸ represents an aromaticheterocycle selected from the group consisting of: imidazolyl,benzimidazolyl, triazolyl, and tetrazolyl, wherein the heterocycle isunsubstituted or substituted with a substituent selected from the groupconsisting of: C₁₋₆ alkyl, C₁₋₆ alkoxy, phenyl, oxo, thioxo, halo,trifluoromethyl, trimethylsilyl, --NR^(a) R^(b), --NR^(a) COR^(b),--CONR^(a) R^(b), --CO₂ R^(a), --SR^(a), --SOR^(a), --SO₂ R^(a), and--CH₂ OR^(a) ; and R^(a) and R^(b) are each independently selected fromthe group consisting of: hydrogen, trifluoromethyl, C₁₋₆ alkyl,unsubstituted phenyl and phenyl substituted by a substituent selectedfrom the group consisting of C₁₋₆ alkyl, halo and trifluoromethyl. 2.The compound according to claim 1 wherein R¹ represents phenylsubstituted by one or more substituents selected from the groupconsisting of: C₁₋₄ alkyl, trifluoromethyl, and halo.
 3. The compoundaccording to claim 1 wherein R⁸ is an aromatic heterocycle selected fromthe group consisting of: imidazolyl, benzimidazolyl, triazolyl, andtetrazolyl, wherein the aromatic heterocycle is substituted by oxo orC₁₋₆ alkyl.
 4. The compound according to claim 1 wherein R⁸ is anaromatic heterocycle selected from the group consisting of:unsubstituted triazolyl, triazolyl substituted by oxo, and triazolylsubstituted by thioxo.
 5. A compound selected from the group consistingof:2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]benzimidazole;5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]tetrazole;5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-4-methyl-3-thioxo-1,2,4-triazole;3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole;5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole;5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methyltetrazole;5-[((2R*,3R*)3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyltetrazole;3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole;5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-thioxo-1,2,4-triazole;2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-(p-toluenesulphonyl)imidazole;2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]imidazole;4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]imidazole;5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]tetrazole;5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methyltetrazole;5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyltetrazole;5-[((2S,3S)-3-((3-t-butyl-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;2-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]imidazole;5-[((2S,3S)-3-((3-chloro-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3-t-butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3,5-bistrifloromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;3-[((2S,3S)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyl-1,2,4-triazole;3-[((2R*,3R*)-3-((3,5-bistrifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-thiomethyl-1,2,4-triazole;5-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-carboxamido-1,2,4-triazole;3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-cyano-1,2,4-triazole;3-[(1S)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;3-[(1R)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;3-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole;5-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-2-phenyl-3-((3-trifluoromethyl)phenyl)methyloxy)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3,4-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3-t-butylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2R*,3R*)-3-((3,5-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;3-(1S)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;3-(1R)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazole;5-(1S)-1-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)ethyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;3-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-triazole;5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(3-chlorophenyl)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3,4-dimethylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3-i-propoxyphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3-fluoro-5-methylphenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[(3-(3R*)-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-methyl-2-(2R*)-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-(3-fluorophenyl)piperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-triazole;andpharmaceutically acceptable salts and prodrugs thereof.
 6. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable carrier therefor.7. The pharmaceutical composition according to claim 6 furthercomprising a bronchodilator.
 8. A method for the treatment or preventionof a physiological disorder associated with an excess of tachykinins,which method comprises the administration to a patient in need thereofof a tachykinin-reducing amount of a compound according to claim
 1. 9.The method according to claim 8 for the treatment or prevention of painor inflammation.
 10. The method according to claim 8 for the treatmentor prevention of migraine.
 11. The method according to claim 8 for thetreatment or prevention of arthritis.
 12. The method according to claim8 for the treatment or prevention of postherpetic neuralgia.
 13. Amethod for the treatment of a respiratory disease, which methodcomprises administration to a patient in need thereof of an effectiveamount of a compound according to claim 1 and an effective amount of abronchodilator.